HGMD_global_document - BIOBASE Biological Databases
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1. Human Homo sapiens Genome Browser Gateway The UCSC Genome Browser was created by the Genome Bioinformatics Group of UC Santa Cruz Software Copyright c The Regents of the University of California All rights reserved group genome assembly position search term Mammal Human Feb 2009 GRCh37 hg19 chrX 70 749 865 70 749 900 enter position gene symbol or search terms submit Click here to ass prewees user interface settings to their defaults track search ackhubs configure tracks and display Figure 11 Adding a custom track at UCSC Genome Browser HGMD Global Documentation 09 2015 34 Step 3 Finding the Custom Genome Browser track to upload e Click Browse Figure 12 and upload previously saved browser track Click submit Add Custom Tracks clade Mammal genome Human assembly Feb 2009 GRCh37 hg19 Display your own data as custom annotation tracks in the browser Data must be formatted in BED bigBed bedGraph GFF GTF WIG bigWig MAF BAM BED detail Personal Genome SNP VCF broadPeak narrowPeak or PSL formats To configure the display set track and browser line attributes as described in the User s Guide Data in the bigBed bigWig BAM and VCF formats can be provided via only a URL or embedded in a track line in the box below Publicly available custom tracks are listed here Examples are here Paste URLs or data Or upload Browse No file selected Submit a Optional track d2. Results will contain an alphabetical list of HGMD phenotypes and genes associated with your search term You also have the ability to browse the phenotypes found in HGMD alphabetically A Z by chromosome or by mapped UMLS ontologies currently OMIM SNOMED CT MeSH and MTH terms Reference search There are six ways HGMD may be searched for references 1 All fields search Searches for your search terms in all fields listed below 2 6 2 First author search Searches HGMD for the first author surname of the mutation references found in HGMD Example Edwards 3 PubMed journal search Searches HGMD for the PubMed journal title abbreviations associated with the mutation references found in HGMD Full journal names may also be used HGMD Global Documentation 09 2015 19 Example Am J Hum Genet or American journal of human genetics 4 PubMed ID search Searches HGMD for PubMed IDs associated with the mutation references found in HGMD Example 9042910 5 Publication year search Searches HGMD for the specific years in which the mutation references found in HGMD were published Example 1997 6 HGMD gene search Searches HGMD for the gene symbols associated with the mutation references found in HGMD Example TCOF1 Results will contain a list of genes and references associated with your search terms To access the HGMD record for that gene click on the gene symbol listed You may al
3. amp Dimas et al 2009 In some instances the above criteria may be only partially satisfied such that the HGMD curators remain unconvinced as to the functional phenotypic relevance of the variant reported In such cases the polymorphism may be included as a result of i supporting information becoming available subsequent to publication of the original first HGMD Global Documentation 09 2015 12 report or ii because the associated gene disease state was deemed to be of sufficient importance for the variant to warrant further study Such variants have been ascribed the descriptor association with as opposed to association with without a question mark to indicate that some degree of uncertainty is involved Replication studies for disease associated polymorphic variants The replication of disease association studies can be a source of additional information to satisfy the inclusion criteria If a replication study serves to support a previously tenuous genotype phenotype correlation then the phenotype can be promoted from association with to association with and the replication study will be added as a secondary reference HGMD wild type and mutant alleles may be reversed In HGMD the mutant allele is recorded as the allele responsible for the reported disease phenotype In some HGMD records typically polymorphism data where both the wild type and mutant allele may be found at high freque
4. 4 2 O Regulatory Include Exclude location relative to mr p e 9 Include minimum 3 characters Fuzzy Search we Figure 2 Nucleotide Substitutions PLUS Interface HGMD Global Documentation 09 2015 24 How do I search Nucleotide Substitutions can be mined using one or more of the following categories e Motif Search Base Substitution e Amino Acid Substitution e Splicing e Regulatory Other Motif Search Using the drop down box predefined motifs can be selected or a user defined motif can be typed into the text field to the side of the drop down box The user defined motif can be defined by using regular expressions Some characteristics of extended regular expressions are e matches any single character A character class matches any character within the brackets For example abc matches a b or c To name a range of characters use a dash a z matches any letter whereas O 9 matches any digit Example 1 The regular expression CA CA AGGTAGGTAA would match to the 5 splice site consensus sequence Example 2 The regular expression GC ATG would match to both GATG and CATG Example 3 The regular expression AG CT AG would match the sequence RYR Note the motif search feature is not case sensitive and single letter codes are not supported If the check box Created is selected then all substitutions that create this motif will be ret
5. all other HGMD data Retired entry R An entry retired from HGMD due to being found to have been erroneously included ab initio or subject to correction in the literature resulting in the record becoming obsolete merged or otherwise invalid HGMD Global Documentation 09 2015 10 Inclusion Criteria for Disease associated Functional polymorphisms Aim HGMD seeks to include DNA sequence variants that are either i disease associated and of likely functional significance or ii of clear functional significance even though no associated clinical phenotype may have been identified to date In order to deal with published polymorphism reports describing potential disease associations in a methodical and uniform manner we have adopted the inclusion criteria set out below Background At present 58 of the polymorphic variants recorded in HGMD are disease associated However even in cases where no disease association has yet been demonstrated functional polymorphisms that alter the expression of a gene or the structure function of the gene product are potentially very important Although a functional polymorphism with no disease association may not have any direct and or immediate clinical relevance these data are potentially very valuable in terms of understanding inter individual differences in disease susceptibility The vast majority of polymorphic variants in HGMD are single nucleotide polymorphisms SNPs but a smal
6. or 385_386delins 4 Search using dbSNP identifier Searches HGMD for mutations that have a corresponding entry present in the NCBI dbSNP database Partial rs numbers will be accepted with wildcards checked Example rs1799963 Example rs1042522 5 Search using chromosomal coordinates Searches HGMD for mutations using chromosomal coordinates This search includes only then missense nonsense mutations small deletions small insertions and small indels that have HGMD Global Documentation 09 2015 18 been mapped to the genome the February 2009 build GRCh37 hg19 Users may enter a coordinate range a single coordinate or an entire chromosome Example chr1 2327114_2333800 Example chrX 77130681 77132008 Example chr7 1942983 Example chr2 Phenotype search There are two ways HGMD may be searched for phenotypes 1 HGMD phenotype search Searches the phenotypes recorded in HGMD directly The phenotypes present in HGMD are generally recorded as they were initially reported in the corresponding literature article Example Cancer NOTE You can restrict your search to disease causing mutations or disease associated functional polymorphisms The default is to search both types Please note that for convenience frameshift or truncating variant is included under both types 2 UMLS semantic search Searches mapped UMLS ontology which includes OMIM SNOMED CT and MeSH terms Example Cutis laxa
7. will return all results containing breast OR cancer Note2 HGMD fulltext searching in MySQL has a minimum word length of 4 characters by default Any search terms entered with less than 4 characters may not be recognised by the HGMD fulltext search engine Non boolean searching This type of search works in a different way to the Boolean fulltext search The fulltext index is not utilised therefore there is no minimum word length in force 2 and 3 character searches will function No operators are used and multiple search terms will be treated as a literal phrase Partial matches will also be returned by the search except for the HGNC OMIM GDB Entrez ID search will return exact matches only Search for the word transporter e Returns results where the word transporter is present Will also return partial matches such as transporters and cotransporter Search for the words prostate cancer e Returns results where the words prostate cancer occur as a literal phrase Search for the gene symbol APC Returns results where APC occurs including the APC gene itself plus partial matches e g APCDD1 and PROC where APC is an alias Note This search does not utilise an index and therefore may be somewhat slower than a Boolean fulltext search Gene search Enter search term The genes present in HGMD may be found by utilising seven different search options HGMD Global Documentation 09 2015 16 1 All fields search
8. 618685222 201816155 06186879531 07 8211318127 ses 42 525 aaa El reg 42 525 590 42 526 000 42 526 508 rchTrack_32_variants_hg19 CM994691 601892492 6019583355 21992872 20155 8334 21887958 601687952 CM96 8483 601999351 21994598 01994689 UCSC Genes RefSeq GenBank CCDS Fran TRNAS amp Comparative Genomics 968482 61988851 61887929 Um um mm am um o mm o EM EE RefSeq Genes RefSeq Genes MEI ENNI uum Red a um Publications Sequences in Scientific Articles Sequences Hmmm pa SNPs l Wo Human mRNAS from GenBank Human mRNAS AAA Human ESTs That Have Been Spliced Spliced ESTs m 106 _ H3k27Ac Mark Often Found Near Active Regulatory Elements on 7 cell lines from ENCODE Layered H3k27Ac G 8 8 alo j Digital DNasel Hypersensitivity Clusters in 125 cell tupes from ENCODE ONase Clusters AAA AS Transcription Factor ChIP seq 161 factors from ENCODE with Factorbook Motifs Txn Factor ChIP 4 86 166 vertebrates Basewise Conservation by Phy lor 188 Vert Cons Mu tul l aes Ale AN Wer d i more Tn 4 5 Figure 134 An Advanced Search result been viewed on the UCSC genome browser Note Large custom tracks may take a while to load HGMD data HGMD custom annotation tracks can be viewed only on the machine from which they were uploaded and are automatica
9. Functional profiling result 6 Disease Phenotype 7 Gene symbol 8 Entrez gene id 9 Link to PROTEOME locus report 10 HGVS nomenclature 11 Mutation description 12 Genomic coordinates hg19 default 13 MutPred 14 SIFT 15 Genomic sequence context 16 Primary Reference 17 Mutation viewer link Functional Profiling of Mutation Data HGMD is in the process of annotating variants with both in vitro in vivo and in silico data to help in the ascertainment of the molecular mechanism underlying the functional effect of a given mutation When this process has been completed HGMD aims to annotate mutation data for over 40 different types of functional site including exonic splice enhancers ESE post translational modification sites and numerous transcription factor binding sites TFBS etc Please see the following paper for more information Mort M Evani US Krishnan VG Kamati KK Baenziger PH Bagchi A Peters BJ Sathyesh R Li B Sun Y Xue B Shah NH Kann MG Cooper DN Radivojac P Mooney SD In silico functional profiling of human disease associated and polymorphic amino acid substitutions Hum Mutat 31 3 335 346 HGMD Global Documentation 09 2015 27 Access to the functional profiling search tools is via the Nucleotide Substitutions Plus Search An example functional profiling search Search for HGMD regulatory variants disrupting transcription factor binding sites TFBS from TRANSFAC Select TF
10. Ru RL E ATTOGRAA T A TA T T G A ACA A CARAGA A G G 100 TTGTCAGACATATACCAAATCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGAAAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAAT L S D I IP SVD SA DH LS EELER EW DR EL AS KKH G TT E TGT C AA TA TA T T CA T A c A G 199 CCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTTCTATGGAATCTTTTTATATTTAG P KL IH AL R R CF FW R FM F Y 6 I FL TA A TC T GGAAGTCACCAAAGCAGTACAGCCT E V T K A V Q P Figure 14 CFTR gene as displayed by the Mutation Viewer HGMD Global Documentation 09 2015 38 Mutation Viewer examples Nucleotide Substitution Example Leu Arg CTT CGT codon 51 GGACTIGGT L G GGACTTGGT L GGACGTGGT R Insertion Example CCTGAAA GATagatATTAATTTCA codon 94 TCCTGAAAGATATTAATTTCAAGATA AGAT TCCTGAAAGATATTAATTTCAAGATA TCCTGAAAGAT AGAT ATTAATTTCAA Deletion Example CGATT GAAGaagCAATGGAA codon 141 GAAGAAGCAATGGAA BAG GAAGAAGCAATGGAA GAAGCAATGGAA HGMD Global Documentation 09 2015 39 Indel Example ATTT CCCtgggctGTA codon 59 Insert A ATTTCCCTGGGCTGTA A ATTTCCCTGGGCTGTA ATTTCCCAGTA HGMD Global Documentation 09 2015 40 Copyright Notice The Human Gene Mutation Database constitutes the intellectual property of Cardiff University Any unauthorised copying storage or distribution of this material without written permission from the curators would lead to copyright infringement with possible ensuing litigation Copyright O Cardiff University 2011 All
11. associated disease state as specified in that report and the gene name and official symbol as recommended by the HUGO Gene Nomenclature Committee HGNC In cases where no official gene symbol exists a provisional symbol has been assigned by the HGMD curators which is denoted by lower case letters NCBI dbSNP numbers where identified may also be recorded The inclusion of a dbSNP identifier for a HGMD entry in no way implies that the entry in question is a polymorphism Missense nonsense Single base pair substitutions in coding regions are presented in terms of the triplet change Splicing Single base pair substitutions with consequences for mRNA splicing are presented as the nucleotide change and the position relative to the donor or acceptor splice site of a specified intron Positions given as positive integers refer to a 3 downstream location and negative integers refer to a 5 upstream location HGMD Global Documentation 09 2015 8 Regulatory Substitutions causing regulatory abnormalities are logged with thirty nucleotides of upstream and downstream flanking sequence the location of the mutation relative to the transcriptional initiation site start codon or termination codon is given Small deletions Micro deletions of 20 bp or less are presented with the deleted bases in lower case plus in upper case 10 bases of sequence flanking both sides of the lesion The numbered codon is preceded in the given
12. be considered as giving rise to a deficiency or occasionally a surfeit of a given gene transcript or protein product The phenotype recorded in HGMD would give a brief description of the functional effect e g Reduced gene expression association with If at a later date evidence becomes available to indicate that a disease clinical phenotype is associated with the polymorphism the functional phenotype will be replaced by the disease clinical phenotype with the corresponding paper added as the primary reference The earlier functional report will be included as a secondary reference and the entry will be re categorised as DFP Polymorphic variants affecting individual drug responses patient survival times after diagnosis and responses to surgical intervention are not included in HGMD Studies which simply report dbSNP numbers in association with disease e g from large scale genome wide association studies with no additional evidence of direct functional involvement are also not included in HGMD Users interested in this particular category of variation should try other databases such as the Catalogue of Published Genome Wide Association Studies http www genome gov 26525384 or the Genetic Association Database http geneticassociationdb nih gov One caveat to bear in mind is that in vitro studies are not invariably accurate indicators of the in vivo situation see for example Cirulli and Goldstein 2007
13. clearly involved in the disease association Risk haplotypes Reports of haplotypes associated with an increased risk of disease are not included in cases where there is no indication as to precisely which variant or variants within the haplotype is are responsible for the disease HGMD Global Documentation 09 2015 13 association functional effect If however evidence is presented to support the contention that a single variant within the risk haplotype is causative and or of functional significance to a degree which satisfies the inclusion criteria then it would be included in HGMD HGMD Global Documentation 09 2015 14 Web Interfaces HGMD PRO HGMD Advanced Have I got the right browser The HGMD web pages should work correctly with any modern browser These include the most popular browsers such as Microsoft Internet Explorer Mozilla FireFox and Opera Text only browsers such as Lynx can also operate HGMD correctly although some pages will look odd We are working toward making our code compliant with HTML v5 If your browser is not capable of this it will only mean that the presentation on your screen is not identical to ours The results generated from search requests should not be affected Can I bookmark a particular page With web browsers it is possible to bookmark individual pages from HGMD However we do not recommend this as not only are you likely to miss important notices placed on the HGMD
14. herr e Rr hora ar tae 13 Web Interfaces HGMD PRO HGMD Advanced isssssese emere hene 15 HGMD PRO searches ER 15 GONE SEAMEN REPARA 16 18 Mutation Search PPP diri casino sii 19 4 Phenotype search ie 19 E 8 14 861661566 56316 HGMD Global Documentation 09 2015 Batch Sears 20 Other Search OPtiONS ii lis 20 E NOME Em 21 HGMD Advanced Searches cccssccccssccceeeceseececeecceseececeecceseceseecesseceseecesaescesecesneeenaes 22 Nucleotide Substitutions PLUS search cionales 23 Micro lesions Insertions Indels and Deletions 21bp search 29 Quick search Search in both Nucleotide substitutions and Micro lesions sss 30 MutationMart batch mode search 31 IGeNe DaSSG SCAM Mene 32 Genome interpretation and NGS based analysis using HGMD Advanced 32 Mutation VIEWER aii o A a at A a io 37 eelef 40 FRET RS TACOS nia O 41 HGMD Global Documentation 09 2015 Introduction Citing HGMD If you refer to HGMD in any publication please cite Stenson PD Mort M Ball EV Shaw K Philips A and Cooper DN 2014 The Human Gene Mutation Database building a comprehensive mutation repository for clinical and molecular genetics diagnost
15. other information e g in vitro or in vivo expression functional data replicated association studies epidemiological studies evolutionary conservation data etc should have been made available to support the contention that the polymorphism in question is itself of bona fide functional significance Such a polymorphism DP could have consequences for gene expression protein structure function gene splicing etc These supporting experimental data are required to ensure that non causative variants i e those merely in linkage disequilibrium with the actual causative variants are not included If the functional data required to support the inclusion of a disease associated variant are contained in a subsequent article the primary reference logged in HGMD will be that in which the disease association was reported with the paper containing the functional evidence being given as a secondary reference Functional characterisation Polymorphisms of functional significance with no reported disease association FP If no clinical phenotype is known to be associated with a polymorphic variant but sufficient in vitro or in vivo expression functional datal have nevertheless been presented to indicate functional significance then the variant will be included in HGMD Typically such data provide evidence for a direct effect on gene expression protein structure and or function gene splicing etc These variants can thus in a very real sense
16. sequence by the caret character Where deletions occur outside the coding region of the gene other positional information is occasionally provided e g 5 UTR 5 untranslated region or E6l6 denotes exon 6 intron 6 boundary Small Insertions Micro insertions of 20 bp or less are shown with the inserted bases in lower case and 10 bases of upstream and downstream sequence in upper case The numbered codon is preceded in the sequence by the caret character Where insertions extend outside the coding region other positional information may be provided e g 3 UTR 3 untranslated region or E12112 denotes exon 12 intron 12 boundary Small Indels Micro indels of 20 bp or less are presented with the deleted bases in lower case flanked by in upper case 10 bases of upstream and downstream sequence The inserted nucleotides are shown in lower case The numbered codon is preceded in the given sequence by the caret character Where the lesion occurs outside the coding region of the gene other positional information is occasionally provided e g c 252 32_ 28 to indicate that the deleted bases occur at the 32_ 28 positions relative to the exon starting at c 252 Other mutation types For gross deletions gross insertions repeat variations and complex rearrangements information regarding the nature and location of a lesion is logged in narrative form because of the extremely variable quality of the original data report
17. BS from functional profiling drop down menu Figure 3Figure 3 Functional Profiling ES include Exclude in vitro M in silico M Figure 3 Drop down functional profiling menu from Nucleotide Substitutions PLUS Functional sites disrupted by the mutation in question are shown in the functional Profile column Figure 4 highlighted by red box Click Here to Save Results as Text File Click Here to Save Results as Genome Browser Track for GRCh37 ha19 Query returned 445 mutations from 318 different genes Mutation E V t 1 AVES ariani HGMD_ID dbsnp Fanchinnal profile Disease Phenotype class Se AS Regulatory DP CR020828 rs2740483 Transcription Factor Binding Site Reduced risk of coronary artery disease association with Regulatory FP CR110380 rs191903738 Transcription Factor Binding Site Reduced transcriptional activity Figure 4 Functional profiling results Clicking on the relevant functional site shows the functional profiling mutation report Figure 5 which displays both in vitro in vivo and in silico evidence where available for any functional site disruption HGMD Global Documentation 09 2015 28 Publiyed 8 No annotated articles in Pubmed reporting this variant located at In vitro in vivo literature evidence of functional site disruption for CRO20828 Spl TFBS Sony no published in vitro in vivo evidence bio DE In silico evidence that this variant overlaps with I an Sp1 TFB
18. For example entering cancer as a disease phenotype search term will produce too many results Narrowing it to something like gastric cancer may produce the desired results Note also that there is a minimum word length of 4 characters for HGMD searching so entering any term with less than that will not produce any results HGMD Global Documentation 09 2015 22 HGMD Advanced searches Search types The HGMD Advanced Search has five different interfaces 1 Nucleotide Substitutions PLUS search 2 Micro lesions search 3 Quick search 4 MutationMart 5 Gene based search Welcome to HGMD Professional version 2014 4 To start a search select one of the tables below or browse disease genes by chromosomal location or enter your Quick Search query d SI 3 This release comprises the following tables Table Description Entries Single base pair substitutions in coding regions substitutions affecting gene regulation and 109077 substitutions with consequences for mRNA splicing Support for hg19 only Includes searching for variants disrupting functional elements e g TFBS from TRANSFAC Micro deletions gt 21bp Micro insertions gt 21bp and Micro indels gt 21bp Support 37272 for hg19 only Beta preview of a batch mode search for HGMD using dbSNP PubMed or Entrez gene identifiers UTATION MART Developed by Matthew Mort Copyright HGMD Figure 1 Access to HGMD Advanced Search In
19. QIAGEN HGMD 2015 HGMD Professional 2015 3 Global Documentation 10009 Sample to Insight QIAGEN Contents dee Te e 4 Citing GMD ee 4 Rationale vs ivonne a 4 Data coverage cities 4 Evidence for pathological authenticity econ vin a e 5 RICH Ee de EE 6 Curation POlCY acom a sans SEENEN DEE ge ENEE ES Eet 6 Mutation 68160611687 guud sre 8 RER nbd nants O sa a 8 Missense Hnonserns cese eut a osados 8 SDpIICIIQ ss O 8 ac HR MT 9 Small ANS ies 9 Small OSOS AR 9 Small le 9 Other mutation PE alitas ala 9 Sub categorisation EE E 10 Disease associated polymorphism DP ENEE ENEE ENEE EEN 10 Disease associated polymorphism with supporting functional evidence DER 10 In vitro laboratory or in vivo functional polymorphism FP esee 10 Disease causing mutation DM eee I e Ie mee eese e mn eme me enne 10 Disease causing mutation DM 0 00 III III In Ie me hehe e me eme n nene eee 10 Retired entiy CR NEE 10 Inclusion Criteria for Disease associated Functional polyMorphismMS oooococccconccronccconccconcnonnnos 11 Other Categories of eoe
20. Rights Reserved HGMD Global Documentation 09 2015 41 References Stenson PD et al 2014 The Human Gene Mutation Database building a comprehensive mutation repository for clinical and molecular genetics diagnostic testing and personalized genomic medicine Hum Genet 133 1 9 Cooper DN et al 2013 Where genotype is not predictive of phenotype towards an understanding of the molecular basis of reduced penetrance in human inherited disease Hum Genet 132 1077 1130 MacArthur DG et al 2012 A systematic survey of loss of function variants in human protein coding genes Science 335 823 828 Dimas AS et al 2009 Common regulatory variation impacts gene expression in a cell type dependent manner Science 325 1246 1250 Stenson PD et al 2008 The Human Gene Mutation Database HGMD 2008 Update Genome Med 1 1 13 Cirulli ET and Goldstein DB 2007 In vitro assays fail to predict in vivo effects of regulatory polymorphisms Hum Mol Genet 16 1931 1939 Balakirev ES and Ayala FJ 2003 Pseudogenes are they junk or functional DNA Ann Rev Genet 37 123 51 Ng PC and Henikoff S 2001 Predicting deleterious amino acid substitutions Genome Res 11 863 74 den Dunnen JT and Antonarakis SE 2001 Nomenclature for the description of human sequence variations Hum Genet 109 121 24 Cotton RG and Scriver CR 1998 Proof of disease causing mutation Hum Mutat 12 1 3 Krawczak M and Cooper DN 1995 Core datab
21. S from TRANSFAC Extra Info VSSP1 Q2 01 Sp1 T00754 Sp1 Species rat Rattus norvegicus T00752 Sp1 Species mouse Mus musculus T00759 Sp1 Species human Homo sapiens T0B484 Sp1 Species human Homo sapiens T09431 Sp1 Species rat Rattus norvegicus T09118 Sp1 isoform 1 Species mouse Mus musculus T02356 Sp2 Species human Homo sapiens T02453 Sp3 Species rat Rattus norvegicus T02338 Sp3 Species human Homo sapiens T09426 Sp3 isoform1 Species human Homo sapiens T02339 Sp4 Species human Homo sapiens Figure 5 Functional profiling mutation report Ability to download results Figure 6 1 Results downloaded as a tab delimited file 2 Genome browser track using hgl9 coordinates B IO BAS E NUCLEOTIDE BIOLOGICAL DATABASES lt 4 Query returned 452 mutations trom different genes Mutatio 5 Variant HGMD ID dbsnp Disease Phenotype type class Missense DP CM980001 rs669 Alzheimer disease association with Same sense DP 0611032792 2 Alzheimer disease association with Figure 6 Downloading results from an Advanced Search query HGMD Global Documentation 09 2015 29 Micro lesions Insertions Indels and Deletions 21bp search This category comprises all small deletions small insertions and small indels This allows data mining to be performed on a number of fields including deletion size insertion size and user defined motifs download using the sa
22. S researchers Data coverage The Human Gene Mutation Database includes the first example of all mutations causing or associated with human inherited disease plus disease associated functional polymorphisms reported in the literature HGMD may also include additional reports for certain mutations if these reports serve to enhance the original entry e g functional studies These data comprise various types of mutation within the coding regions splicing and regulatory regions of human nuclear genes Somatic mutations and mutations in the mitochondrial genome are thus not included although in the latter case links to Mitomap are provided Each mutation is entered only once in order to avoid confusion between recurrent and identical by descent lesions HGMD Global Documentation 09 2015 4 HGMD does not usually include mutations lacking obvious phenotypic consequences although a few such variants have been included where they could conceivably have some clinical effect e g albumins butyrylcholinesterases Many published mutation searches identify more than one genetic change in a single patient In such cases the relationship between a given lesion and the clinical phenotype is not always immediately clear and the curators of HGMD have had to rely exclusively upon the judgements of authors peer reviewers and journal editors The possibility of unintentional inclusion of some lesions with little or no pathological significance can ther
23. Searches for your search terms in all fields listed below at once 2 7 2 Gene symbol search Searches HGMD for the official HUGO Gene Nomenclature Committee gene symbol Any gene symbol aliases that have been identified are also be included in this search Official symbol example ABCC2 Gene symbol alias example MRP2 3 Gene description search Searches HGMD for the official HUGO Gene Nomenclature Committee gene name Any gene name aliases that have been identified are also be included in this search Official description example ATP binding cassette sub family C CFTR MRP member 2 CMOAT Gene description alias example Canalicular multispecific organic anion transporter 4 Chromosomal location search Searches HGMD for the chromosomal location of HGMD genes Example 10q24 5 HGNC OMIM GDB Entrez ID Searches HGMD for the gene identifiers assigned by the HUGO Gene Nomenclature Committee database Online Mendelian Inheritance in Man the Genome Database legacy only and the Entrez Gene database HGNC Example 5384 OMIM Example 601107 GDB Example 6089489 Entrez Example 1244 6 Disease phenotype search Searches HGMD for the disease phenotype associated with reported mutations in HGMD genes Example Dubin Johnson syndrome 7 Gene ontology search Searches for the ontology terms that have been assigned by the Gene Ontology Consortium to the genes present in HGMD Example org
24. T Beta preview of a batch mode search for HGMD using dbSNP PubMed or Entrez gene identifiers Developed by Matthew Mort Copyright HGMD Figure 8 HGMD Advanced Quick Search HGMD Global Documentation 09 2015 31 Quick search examples Example 1 Enter Japanese as the search term Figure 8 This returns all mutations linked to a Mutation Report with Japanese in the title and or Japanese in the Gene or Disease fields Example 2 Enter stroke candidate gene as the search term This returns all mutations linked to a Mutation Report with stroke candidate gene in the title and or stroke candidate gene in the Gene or Disease fields MutationMart batch mode search HGMD can be queried in a batch mode using three different types of identifier 1 dbSNP identifier e g rs1800072 2 PubMed identifier e g 20981092 3 Entrez gene identifier e g 1080 Up to 50 identifiers can be queried at once place each identifier on a new line MutationMart Results can be downloaded to a tab delimited text file HGMD Global Documentation 09 2015 32 BIOBQSE MutationMart Quick Search 1 Select the type of input identifiers Substitutions 1 Select source input format dbSNP identifier e g rs1800072 Micro lesions Mart 2 Paste a list of identifiers one or more into the text area below one identifier per lme Professional rs3216733 1557412392 rs34002892 rs8191962 2 Paste a list of id
25. anic anion transmembrane transporter activity GO 0008514 or 0008514 Detailed results will contain a list of gene information diseases and external links IDs associated with your search terms Concise results are limited to gene information symbol description chromosomal location only To access the HGMD record for a gene click on the gene symbol listed Some portions of the returned text may be highlighted in green This indicates the part of the results that matches the search terms Secondary gene search Symbol The secondary search allows users to go directly to a particular gene if the gene symbol is known This search will only function with the correct HUGO Nomenclature Committee gene symbol HGMD Global Documentation 09 2015 17 Mutation search There are five ways HGMD may be searched for specific mutations 1 Codon number search Searches for mutations affecting a particular codon in the coding region This search will return results from the missense nonsense small deletions small insertions and small indels mutation categories Results will contain a list of genes diseases with links to both the gene page and specific mutations found during your search For small deletions small insertions and small indels the codon number searched is that of the first affected codon not the last whole codon as marked by in the HGMD entry i e in the entry CDO10589 AAAS 156 TTGCGT GTCTttGCATGGCACC the first affe
26. ase Nature 374 6521 402 Cooper DN and Krawczak M 1993 Human Gene Mutation BIOS Scientific Publishers Oxford HGMD Global Documentation 09 2015 42
27. ation of reduced gene expression mRNA splicing activity or stability of protein product consequent to mutation Demonstration that the mutant protein has the same properties in vitro as its in vivo mutant counterpart Reversal of the pathological phenotype in patient cultured cells by gene replacement Despite the best efforts of the HGMD curators it may be assumed that some categories of gene lesion listed in HGMD e g missense mutations regulatory mutations splicing mutations are likely to include entries that are not actually causative even though they have been reported as such In some cases the evidence for pathogenicity may be dubious such variants can be identified by the addition of a question mark to the given disease phenotype which indicates that some degree of uncertainty is involved HGMD Global Documentation 09 2015 5 Data collection Data are collected by the manual and computerised screening of journals and publicly available locus specific databases LSDBs Where possible data are included from the original reports entries are referenced to Mutation Updates and review articles if the original publication is not available Please note that ambiguously described mutations are not included in the database until clarification has been obtained from the authors Curation policy Disease causing mutations are entered into HGMD where the authors of the associated reference indicate that the alteratio
28. cted codon is 157 Please note that this search will not pick up mutations either beginning or wholly within an intron as there will not be a first affected codon to search for Example 157 NOTE You can restrict your search to disease causing mutations or disease associated functional polymorphisms The default is to search both types Please note that for convenience frameshift or truncating variant is included under both types 2 Accession number search Searches HGMD for specific accession numbers if known Partial accession numbers will be accepted with wildcards Results will contain a list of genes with links to both the gene page and specific accession number s found during your search Example CMO35497 or CMO35x 3 Search using official HGVS mutation nomenclature Searches HGMD for mapped mutations using the official nomenclature as described by den Dunnen and Antonarakis 2001 This search includes only the missense nonsense mutations small deletions small insertions and small indels that have been mapped to the genome Please note that for deletions insertions and indels HGVS nomenclature requires that the most 3 affected nucleotides are specified Example 298C gt T or R100X Example 20_21delTT or 20 21del2 or 20_21del Example 104_105insAA or 104_105ins2 or 104_105ins and 2195_2198dupAACA or 2195 2198dup4 or 2195 2198dup Example 385_386delAGinsGTT or 385 386del2ins3
29. ed HGMD Global Documentation 09 2015 9 Sub categorisation of data Disease associated polymorphism DP A polymorphism reported to be in significant association with a disease phenotype p 0 05 that is assumed to be functional e g as a consequence of location evolutionary conservation replication studies etc although there is as yet no direct evidence e g from an expression study of functional effect Disease associated polymorphism with supporting functional evidence DFP A polymorphism reported to be in significant association with disease p lt 0 05 for which evidence of direct functional importance e g as a consequence of altered expression mRNA studies etc has been presented either in the original report or in a subsequent study which will be included as a secondary reference In vitro laboratory or in vivo functional polymorphism FP A polymorphism reported to affect the structure function or expression of the gene or gene product but with no disease association reported as yet Disease causing mutation DM Likely pathological mutation reported to be disease causing in the corresponding report but where the author has indicated that there may be some degree of doubt or subsequent evidence has come to light in the literature calling the deleterious nature of the variant into question Disease causing mutation DM Pathological mutation reported to be disease causing in the corresponding report i e
30. efore not be ruled out HGMD includes disease associated functional polymorphisms To be included there must be a convincing association of the polymorphism with the disease functional phenotype More information on this can be found in the polymorphism inclusion criteria Evidence for pathological authenticity Pathological mutations that dramatically disrupt the structure of a given gene are self evidently very likely to be responsible for the associated clinical phenotype However for other categories of lesion pathological mutations are often difficult to distinguish from polymorphisms with little or no clinical significance particularly if their structural or functional consequences are subtle Cotton and Scriver 1998 Evidence for their authenticity in a pathological context therefore usually comes from one or more different lines of evidence Absence in normal controls Novel appearance and subsequent cosegregation of the lesion and disease phenotype through the family pedigree Absence of any other lesion in the gene that could be responsible for the observed clinical phenotype Previous independent occurrence in an unrelated patient Non conservative amino acid substitutions are more likely to disrupt protein function Location in a protein region of known structural or functional importance Location in an evolutionarily conserved nucleotide sequence and or amino acid residue n vitro demonstr
31. entifiers Information KE 1517235416 Contact us r55882115 r 3834129 r53838646 r 11327935 r533989964 zs 511355796 3 Click Search HGMD 753842620 rs 16989366 rs11575899 r 35325636 1562568989 1534391539 kee 4 View and or Download the results SEARCH HGMD RESET MART RESULTS 18 VARIANT FOUND Download Results as Textile AAA 153216733 coosa353 Bipolar disorder assoc with for SPAS Figure 9 Description of the MutationMart Gene based search Clicking on a chromosome identifier 1 22 X Y MT will return a list of all the genes on that chromosome recorded in HGMD The list will include links to the Mutation Viewer for the genes in which substitutions small deletions small insertions and or small indels in the coding region are recorded Genome interpretation and NGS based analysis using HGMD Advanced HGMD Advanced provides a collection of utilities to assist in the analysis of NGS data 1 Results from the Nucleotide Substitutions PLUS search Micro lesions search and Mutation Mart can be exported into custom genome browser tracks to allow importing into other software tools such as the UCSC genome browser and Genome Trax 2 Functional profiling of mutation data to identify the underlying molecular mechanism including the mapping of HGMD variants to TFBS from Transfac 3 Providing annotations from SIFT Sorting Intolerant From Tolerant 4 Providing a
32. home page but we reserve the right to change the internal structure of the database as required HGMD PRO searches There are five primary searches in HGMD PRO Gene Mutation Reference Batch and Advanced The Gene and Reference searches support Boolean searching with the use of wildcards UK and US spelling variations are accepted for example both haemophilia and hemophilia will return the F8 and F9 genes Please note that alternate spelling functions only for whole words Boolean fulltext searching operator indicates that the search term must be present in each result e g breast cancer returns results where both breast and cancer are present operator indicates that the search term must not be present in any result e g breast cancer returns results that contain cancer but not breast operator serves as the truncation or wildcard Unlike the other operators it should be appended to the word to be affected HGMD Global Documentation 09 2015 15 e g poly returns results such as polyposis polycystic and polypeptide operator when used to enclose your search terms means that the search terms are treated literally as they were typed e g hum mutat will return results containing the exact phrase hum mutat Note1 If Boolean operators are not utilised then multiple search terms are treated by a Boolean search as separate entities e g a search for breast cancer without quotes
33. ic testing and personalized genomic medicine Hum Genet 133 1 9 Rationale Human gene mutation is a highly specific process and this specificity has important implications for the nature prevalence and therefore diagnosis of genetic disease Indeed the recognition that certain DNA sequences are hypermutable has yielded clues as to the endogenous mutational mechanisms involved and provided insights into the intricacies of the processes of DNA replication and repair Cooper and Krawczak 1993 In practical terms a fuller understanding of the mutational process may prove important in molecular diagnostic medicine by contributing to improvements in the design and efficacy of mutation search procedures and strategies in different genetic disorders The Human Gene Mutation Database HGMD represents an attempt to collate known published gene lesions responsible for human inherited disease This database whilst originally established for the study of mutational mechanisms in human genes Cooper and Krawczak 1993 has now acquired a much broader utility in that it embodies an up to date and comprehensive reference source to the spectrum of inherited human gene lesions Thus HGMD provides information of practical diagnostic importance to i researchers and diagnosticians in human molecular genetics ii physicians interested in a particular inherited condition in a given patient or family iii genetic counsellors iv personal genomics and NG
34. identifiers Example 2153 9 OMIM ID Searches for genes with specified OMIM gene identifiers Example 612309 Other search options The ability to browse HGMD genes by gene symbol A Z chromosomal location 1 22 X and Y or to view pre queried HGMD data a random HGMD gene entry genes newly added for the current release genes updated with new mutation data for the current release genes by total number of mutations or genes sorted by ontology term is also available HGMD Global Documentation 09 2015 21 F A Q search The HGMD Frequently Asked Questions accessed through the Information menu may be searched for keywords or retrieved in its entirety Boolean operators may be used see above and as with HGMD searching there is a minimum word length in force usually of 4 characters General remarks Firstly always make sure you are searching with the correct option selected You cannot use a gene symbol search to find a disease If you are getting error messages you need to alter your search strategy If you are getting too many gene not found errors when searching for gene symbols you should try searching alternate fields instead For example CD95 is the old symbol for FAS It will not appear in a gene symbol search but it will appear in a gene description or alias search If you are not getting the results required when using a gene description or disease phenotype search you can try to narrow your search
35. l number are of the insertion deletion type The polymorphic variants logged in HGMD are generally located in either regulatory or coding regions of genes although it should be noted that SNPs occurring outside of these regions may nevertheless still have consequences for gene expression splicing transcription factor binding etc Definitions The distinction between a disease associated polymorphism and a pathological mutation is in practice often fairly arbitrary and is generally made in the context of the prevalence of the variant in the population as well as its penetrance the frequency with which a specific genotype manifests itself as a given clinical phenotype Variants with a minor allele frequency of gt 1 in the population being studied are by convention termed polymorphisms These polymorphisms are identified in the database by the addition of association with and association with to the clinical laboratory phenotype description the question mark indicates that the association is judged by the HGMD curators to be somewhat tenuous HGMD Global Documentation 09 2015 11 Polymorphic variants logged in HGMD usually fall into two discrete categories Disease associated polymorphisms of presumed or proven functional significance DP or DFP To be included as disease associated a statistically significant p lt 0 05 association between the polymorphism and a clinical phenotype must have been reported In addition
36. lly deleted if unused for 48 hours The HGMD custom annotation tracks are for the sole use of HGMD Professional subscribers Tools used to predict harmful missense mutations SIFT and MutPred HGMD missense mutations have been annotated with two different tools which predict the pathogenicity of missense mutations The MutPred tool also makes predictions about the underlying molecular mechanism disrupted e g phosphorylation site SIFT Sorting Intolerant From Tolerant loss of SIFT predicts whether an amino acid substitution AAS affects protein function based on sequence homology and the physical properties of amino acids NG and Henikoff 2001 For disease causing DM missense mutations in HGMD around 80 are predicted to be deleterious by SIFT An AAS with a SIFT score of less than 0 05 is predicted to be deleterious one with a score greater than or equal to 0 05 is predicted to be tolerated For more information please refer to the SIFT website http sift jcvi org www SIFT help html HGMD Global Documentation 09 2015 36 MutPred The MutPred Score is the probability expressed as a figure between O and 1 that an AAS is deleterious disease associated A missense mutation with a MutPred score gt 0 5 could be considered as harmful whereas a MutPred score gt 0 75 should be considered a high confidence harmful prediction The MutPred hypothesis refers to the underlying struct
37. me method as with the Nucleotide Substitutions Plus search BIOBASE BIOLOGICAL DATABASES HGMD Nucleotide Deletions Insertions and Indels 21 bp n HELP Search Fields Search Terms Refine Search O motif search 9 Include Select output fields pre defined motifs or input user defined motif Created Y Abolished Y e Deletion Insertion size include Exclude Order by Deletion size bp Insertion size bp Gene Symbol v a e Cal 0 Deleted Inserted bases Include 0 Include mutation type s Deleted bases Inserted bases Deletion 7 Insertion v Other Include Indel v dbSNP Identifier Disease phenotype minimum 3 characters Gene symbol 5 Fuzzy Search vj iN MySQL Copyright Matthew Mort HGMD amp Figure 7 Micro lesions search page Output fields include Search results are available to Mutation type HGMD ID dbSNP Disease Phenotype Gene HGVS Genomic coordinates Sequence context codon Deleted bases Inserted bases Nucleotide Reference HGMD Global Documentation 09 2015 30 Quick search Search in both Nucleotide substitutions and Micro lesions With the Quick search selected fields in different tables Nucleotide substitutions and Micro lesions can be searched at the same time This search also queries the title of the original mutation report for key
38. n described confers the clinical phenotype specified upon the individuals concerned Disease associated polymorphisms DPs are entered into HGMD where there is evidence for a significant association with a clinical or laboratory phenotype along with additional evidence that the polymorphism is itself of likely functional relevance e g missense change alters transcription factor miRNA binding site etc Functional polymorphisms FPs are entered into HGMD where the authors have demonstrated that the polymorphism in question exerts a direct functional effect e g as evidenced by a luciferase reporter gene assay Disease associated polymorphisms with supporting functional evidence DFPs must meet both of the above criteria The HGMD curators have adopted a policy of continual assessment of the curated content with respect to the mutation entries in the database If and when additional important new information pertaining to a specific mutation entry becomes available e g questionable pathogenicity confirmed pathogenicity additional phenotypes population frequency functional studies etc the mutation entry may be revised or recategorized Alternatively a comment or additional reference may be added in order to communicate this new information to users Where new information becomes available which suggests that a given disease causing mutation DM entry is likely to be of questionable pathological relevance or even a neutral polymorphism
39. ncy the wild type as given by RefSeq may be the same as HGMD mutant allele this is so we preserve the relationship between reported disease phenotype and mutant allele Other Categories of Variation Copy number variations Copy number variations CNVs are DNA segments gt 1 kb in length that present with variable numbers of copies in a given population These variants are being reported in the literature with an ever increasing frequency CNVs are potentially functionally significant and should therefore in principle be treated by HGMD in a similar manner to any other polymorphism However human CNVs are already being collected by other databases such as the Database of Genomic Variants http projects tcag ca variation and the Human Genome Structural Variation Project http humanparalogy gs washington edu structuralvariation CNVs that are disease associated are also being collated in databases such as DECIPHER http www sanger ac uk PostGenomics decipher the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations http www ecaruca net and the Chromosome Abnormality Database http www ukcad org uk cocoon ukcad Whilst HGMD does not wish to replicate the excellent curatorial work of other organisations HGMD is still interested in such variants if they are shown to be both of functional significance and associated with disease and if they involve a single characterised gene that is itself
40. nnotations from MutPred HGMD Global Documentation 09 2015 33 Option 1 Exporting HGMDY data to other applications e g Genome Trax or UCSC by creating a Custom Genome Browser Track Step 1 Creating your HGMD Custom Genome Browser Track e Use the Advanced Search to generate your search query Click submit and navigate to results page Click download results as genome browser track Figure 10Error Reference source not found Save custom genome browser track to your computer Hint remember where you save it B l 0 B S E B l 0 BAS E NUCLEOTIDE SUBSTITUTION SEARCH RESULTS BIOLOGICAL DATABASES Click Here to Download Results as Text File HGMD Click Here to Download Results as Genome Browser Track gt i wear L Quick Search Query returned 28 mutations from 1 gene Substitutions Mutation DE Gene Baso Micro lesions Varian Disease Phenotype AAA type omg 2001186 symbol coordinates HGVS L build 36 3 Ultrarapid 1 Professional Missense FP 1s769258 metaboliser CYP2D6 chr22 40856707 INM_000106 4 c 31G gt A Ga RE ocio anit NP_000097 p V11M Figure 10 Download custom Genome Browser track Step 2 Importing your HGMD Custom Genome Browser Track into an external program e g UCSC genome browser or Genome Trax e Navigate to UCSC genome browser gateway http genome ucsc edu cgi bin hgGateway Click manage add custom tracks Figure 11Error Reference source not found
41. ocumentation Or upload Browse No file selected Clear Clear Click here for an HTML document template that may be used for Genome Browser track descriptions Figure 112 Uploading the custom Genome Browser track Step 4 e Your track should now be imported e Click go to genome browser Figure 13Error Reference source not found Manage Custom Tracks genome Human assembly Feb 2009 GRCh37 hg19 hg19 Description Type Doc Items Pos add custom tracks AdvancedSearchTrack 32 variants hg19 AdvancedSearchTrack 32 variants hg19 bed 32 chr22 E go to table browser go to variant annotation integrator Figure 123 Imported track HGMD Global Documentation 09 2015 Step 5 View your custom track in the genome browser Figure 14Error Reference source not found UCSC Genome Browser on Human Feb 2009 GRCh37 hg19 Assembly move lt lt lt lt lt gt gt gt J gt gt gt zoom in 1 5x 3x 10x base zoom out 1 5x 3x ls 100x chr22 42 522 613 42 526 763 4 151 bp enter position gene symbol or search terms chr22 413 2 KEIER 12 2 015 1 CREMA 015 51 Scale chr22 CM931123 CMasseas CM876142 26185242 211355526 CYP2D6 cmess215 1 kb 42 523 590 42 524 000 42 524 Cme92491 01853948 01855214 211118698 01938187 201145215
42. on the basis of additional case reports genome population screening studies etc it may be flagged with a question mark DM or even retired from the database entirely if it turns out to have been erroneously included ab initio The majority of clinical phenotypes assigned to DMs in HGMD represent rare conditions that most people would consider to be diseases However it is important to note that HGMD also considers a silent protein deficiency or biochemical phenotype e g butyrylcholinesterase deficiency reduced oxygen affinity haemoglobin etc to be worthy of inclusion since they are potentially disease relevant even if they are relatively common in the general population Such variants may well be assigned to the DM category HGMD users should not assume that just because a mutation is labelled DM that it automatically follows that the HGMD curators are certain that the mutation is disease causing in all individuals harbouring it i e that this mutation is deemed to be fully penetrant As geneticists we know that this is not invariably going to be the case Indeed it is likely that next generation sequencing programmes such as the 1000 Genomes Project will identify considerable numbers of DM mutations in apparently healthy individuals MacArthur et al 2012 Such lesions should not be HGMD Global Documentation 09 2015 6 regarded automatically as being clinically irrelevant because it is quite possible
43. so view the PubMed record if available associated with each search result Secondary reference search Medline journal abbreviation The secondary search allows users to retrieve all data derived from a particular journal HGMD Global Documentation 09 2015 20 Batch search The batch search can be used to search for up to 500 variant or gene identifiers Users should paste or type their list of identifiers into the search box one per line use the radio buttons to indicate the type of identifier and Submit query 1 dbSNP Searches for variants with specified dbSNP rs identifiers Example rs6025 2 Chromosomal coordinate Searches for variants with specified chromosomal coordinates GRCh37 hgl9 Example chr1 169519049 3 Variant Call Format VCF Searches for variants with specified v4 0 compliant VCF The CHROM POS ID REF and ALT tab delimited fields are relevant here Example 1 2338019 ID1 CAG 4 HGMD accession Searches for variants with specified HGMD accession numbers Example CM940389 5 PubMed ID Searches by variants derived from specified PubMed identifiers Example 24077912 6 HUGO gene symbol Searches for genes with specified HUGO Nomenclature Committee gene symbols Example F5 7 HUGO gene ID Searches for genes with specified HUGO Nomenclature Committee gene identifiers Example 3542 8 Entrez Gene ID Searches for genes with specified Entrez Gene
44. terface HGMD Global Documentation 09 2015 23 Nucleotide Substitutions PLUS search Overview The Nucleotide Substitutions PLUS search allows all HGMD single base substitutions missense nonsense regulatory and splicing to be interrogated via one interface The mutation types used by this search have been mapped onto genomic reference sequences hg19 to allow flexible data mining and motif searching for transcription factors conserved DNA domains or user defined motifs BIOBASE BIOLOGICAL DATABASES HGMD Nucleotide Substitutions PLUS d HELP Search Fields Search Terms Refine Search Functional Profiling include Exclude Select output fields functional elements y Mutation Type Variant dass In vitro Y In silico V aa dbSNP 0 Motif search Include Include mutation type s pre defined motifs y Missense Nonsense V or input user defined motif Regulatory V Splicing v Created Abolished Base substitution 9 Include Exclude Include Variant class Wild type Mutant Disease causing mutations All gt Al m Disease associated polymorphisms 9 Include Exclude Functional polymorphisms Amino Acid Wild type Mutant substitution g EME gt A v Filters 9 Include Exclude e SA Intron number Site Location 4 E
45. that these mutations may be low penetrance or late onset disease susceptibility alleles rather than neutral variants It has always been HGMD policy to enter a variant into the database even if its pathological relevance may be questionable while indicating this fact to our users wherever feasible rather than run the risk of inadvertently excluding a variant that may be directly relevant to disease HGMD Global Documentation 09 2015 7 Mutation categories Table 1 Summary of mutation categories in HGMD Types Description Genomic HGVS Web interface coordinates Missense nonsense Single base pair substitutions in coding regions YES YES HGMD PRO and ADVANCED Splicing Single base pair substitutions with consequences for mRNA YES YES HGMD PRO and ADVANCED splicing Regulatory Single base pair substitutions causing regulatory abnormalities YES NO HGMD PRO and ADVANCED Small deletions Micro deletions 20 bp or less YES MES HGMD PRO and ADVANCED Small insertions Micro insertions 20 bp or less YES YES HGMD PRO and ADVANCED Small indels Micro indels 20 bp or less YES YES HGMD PRO and ADVANCED Gross deletions Deletions over 20 bp NO NO HGMD PRO Gross insertions Insertions over 20 bp NO NO HGMD PRO Complex rearrangements Recorded in narrative format NO NO HGMD PRO Repeat variations Recorded in narrative format NO NO HGMD PRO All HGMD entries comprise a reference to the first literature report primary reference of a mutation the
46. ural and functional properties that the missense mutation impacts upon The accompanying P value indicates the assigned probability that the specified structural or functional property has been impacted upon by the mutation a P value lt 0 05 indicates a statistically significant probability Around 20 of missense mutations in HGMD have been assigned a MutPred hypothesis For more information please refer to the MutPred website http mutpred mutdb org about html HGMD Global Documentation 09 2015 37 Mutation Viewer The Mutation Viewer depicts coding region mutations superimposed on the cDNA sequence of a gene The Mutation Viewer is a Java Applet and requires at least Java version 1 5 to be installed Note splicing mutations are not supported by the Mutation Viewer The wild type cDNA sequence is represented in black whilst the mutated nucleotides are shown in different colours Nucleotide Substitutions are shown in RED Deletions are shown in BLUE Insertions are shown in MAGENTA Indels are shown in GREEN The amino acid sequence annotation of the wild type cDNA can be switched on and off with the Show Amino Acids button nissensemonsense Bl Deletions IU insertions L indelis Show Amino Acids G T G P GAAT T X xo T CA CIT T T A c AA T T A 1 ATGCAGAGGTCGCCTCTGGAAAAGGCCAGCGTTGTCTCCAAACTTTTTTTCAGCTGGACCAGACCAATTTTGAGGAAAGGATACAGACAGCGCCTGGAA M QR S PLE KA SV VS KL FF SW T RP ILRES XZ
47. urned If the check box Abolished is selected then all substitutions that disrupt this motif will be returned Base Substitution Using the drop down menus the wild type and or the mutant nucleotides can be selected HGMD Global Documentation 09 2015 25 Amino Acid Substitution Using the drop down menus the wild type and or the mutant amino acids can be selected Splicing Mutations that have been shown to affect splicing can be searched for by e Entering an intron number into the ivs text box The site of the substitution can be selected either donor or acceptor splice site The location relative to the splice site can also be selected Other Select the field to search from the list Enter the search term in the text field If the Fuzzy Search check box is selected then wildcards will be added to the beginning and end of the search term Combining of the other option with the categories listed above will narrow the results to e g to a certain disease phenotype or gene Filters Advanced Search Results can be filtered by mutation type Missense nonsense Regulatory e Splicing Advanced Search Results can also be filtered by variant class Disease causing mutations Disease associated polymorphisms Functional polymorphisms HGMD Global Documentation 09 2015 26 Output Fields 1 Mutation type e g regulatory 2 Variant class e g DM 3 HGMD id 4 dbSNP 5
48. words This search option is especially useful to get a quick overview of the information available in different tables e g for a certain disease The Quick search results are ranked by relevance and are assigned a Ranking rating The quick search ranking score relates to the number of matches found for the query keyword s across the gene symbol disease term title of mutation report abstract of mutation report and dbSNP identifier fields The higher the score the more relevant the mutation to the query keyword s Welcome to HGMD Professional version 2014 4 To start a search select one of the tables below or browse disease genes by chromosomal location or enter your Quick Search query here Gree START ee A ee C wo een v ll E ll gt gt D ee D ess lt Es This release comprises the following tables Table Description Entries NUCLEOTIDE Single base pair substitutions in coding regions substitutions affecting gene regulation and 109077 SUBSTITUTIONS PLUS substitutions with consequences for mRNA splicing Support for hg19 only Includes AE E searching for variants disrupting functional elements e g TFBS from TRANSFAC MICRO LESIONS Micro deletions lt 21bp Micro insertions lt 21bp and Micro indels lt 21bp Support 37272 for hg19 only MUTATION MAR
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