c9446936b026a803d97e7f5128404a327829fe2e max Sun Jul 19 00:01:22 2026 -0700 ClinVar Mapped: add Pfam-domain mapping method Maps ClinVar coding variants through Pfam protein domains as a second method under the clinvarMapped container. Each Pfam family's profile HMM gives a shared coordinate, so a variant inside a domain is projected to the residue in the same HMM match-state column in every other MANE Select gene carrying that domain, then mapped back to that gene's genomic codon. This links genes that share a domain without being paralogs (e.g. the SCN sodium channels and the CACNA1 calcium channels via Ion_trans). Each variant is shown at its 25 most conserved equivalents. Uses Pfam-A 38.2. Adds two alpha subtracks (Pfam Domain Variants, Pfam Domains), the hmmsearch/hmmalign build scripts, autoSql, makeDoc and description page, refs #37883 diff --git src/hg/makeDb/trackDb/human/hg38/clinvarMapped.html src/hg/makeDb/trackDb/human/hg38/clinvarMapped.html index 18b98251b4a..4de91d39a07 100644 --- src/hg/makeDb/trackDb/human/hg38/clinvarMapped.html +++ src/hg/makeDb/trackDb/human/hg38/clinvarMapped.html @@ -1,171 +1,230 @@ <h2>Description</h2> <p> Genes that arose from a common ancestor by duplication, called paralogs, often keep a similar protein sequence and three-dimensional structure long after they have taken on different roles. Because equivalent positions in a family of paralogs tend to play equivalent structural or functional roles, a variant known to cause disease at one position in one gene points to a candidate disease-associated position at the aligned residue in each of its paralogs. This idea, known as <em>paralogue annotation</em>, was introduced for the cardiac ion channel genes and has been used to help classify variants of uncertain significance. </p> <p> This track container takes every ClinVar variant that changes a protein residue -and projects it onto the equivalent residue of each paralog of the gene it -occurs in. It has two parts: +and projects it onto the equivalent residue in related genes. It offers two ways +of deciding which positions are equivalent, and shows the evidence for each. +</p> +<p> +The first method uses <b>paralogs</b>: genes are aligned to the other genes they +descend from by duplication, and a variant is carried to the aligned residue of +each paralog. The second method uses <b>protein domains</b>: many genes share a +conserved domain even when they are not paralogs, and the Pfam profile model of a +domain provides a common numbering for its positions across every gene that +carries it. A variant that falls inside a domain is carried to the same domain +position in every other gene with that domain. Because domains are shared more +widely than paralogy, the domain method reaches relationships the paralog method +does not: for example, a variant in a sodium-channel pore domain is carried both +to the other sodium channels and to the calcium channels, which share the same +domain without being paralogs. </p> <ul> <li><b>Paralog Variants</b> shows, on each gene, the positions that correspond to protein-changing ClinVar variants in that gene's paralogs. Each feature records the source gene, the source variant and its ClinVar classification, and whether the residue is conserved between the two genes.</li> <li><b>Paralog Alignments</b> shows the pairwise protein alignments that were used to transfer the positions, so that the evidence behind any mapped variant can be inspected directly.</li> + <li><b>Pfam Domain Variants</b> shows, on each gene, the positions that + correspond to protein-changing ClinVar variants at the same domain position in + any other gene sharing that Pfam domain. Each feature records the source gene + and variant, the domain and the domain position, and whether the residue is the + same as in the source gene.</li> + <li><b>Pfam Domains</b> shows the Pfam domains found on each gene, the footprint + over which the domain method can carry variants.</li> </ul> <p> -The mapping is purely positional: it indicates that a residue is the alignment -equivalent of a position that is variant in a paralog. It does not itself assign -pathogenicity, and a projection is only as reliable as the underlying alignment, -so the percent-identity and residue-conservation fields should be used to judge -confidence. +The mapping is purely positional: it indicates that a residue is the equivalent, +by alignment or by shared domain position, of a position that is variant in a +related gene. It does not itself assign pathogenicity, and a projection is only as +reliable as the underlying alignment, so the residue-conservation field, and for +paralogs the percent-identity fields, should be used to judge confidence. </p> <h2>Display Conventions and Configuration</h2> <p> In the Paralog Variants track, each feature marks the codon in this gene that aligns to a protein-changing ClinVar variant in a paralog. Features are colored by the ClinVar clinical significance of the source variant: </p> <table class="stdTbl"> <tr><th style="background-color:#D20000;width:2em"> </th> <td>Pathogenic or likely pathogenic</td></tr> <tr><th style="background-color:#00D200;width:2em"> </th> <td>Benign or likely benign</td></tr> <tr><th style="background-color:#000080;width:2em"> </th> <td>Uncertain significance</td></tr> <tr><th style="background-color:#8979D4;width:2em"> </th> <td>Conflicting classifications</td></tr> <tr><th style="background-color:#808080;width:2em"> </th> <td>Other or risk factor</td></tr> </table> <p> These are the same colors used by the ClinVar track. </p> <p> The details page for each mapped variant links to the original ClinVar record and to the position of the source variant on the genome. The track can be filtered by clinical significance, ClinVar review status (0 to 4 stars), molecular consequence, residue conservation (identical, similar or different between the two genes), Ensembl paralog percent identity, and the percent identity of the pairwise alignment. Because most protein-changing ClinVar variants are classified as uncertain, filtering to pathogenic and likely pathogenic classifications and to higher alignment identities is recommended for variant-interpretation use. </p> <p> The Paralog Alignments track shows each pairwise protein alignment as a blocked feature; the label is the partner gene, and the aligned blocks mark the regions that could be compared between the two proteins. </p> +<p> +The Pfam Domain Variants track uses the same clinical-significance colors. Each +feature marks the codon in this gene that shares a domain position with a +protein-changing ClinVar variant in another gene, and its details give the domain, +the domain position, the source gene and variant, and whether the residue is the +same as in the source gene. It can be filtered by source gene, Pfam domain, +clinical significance, review status, molecular consequence and residue +conservation. The Pfam Domains track shows the domain footprints, labeled and +searchable by domain name and gene. +</p> <h2>Methods</h2> <p> Paralog relationships and their percent identities were taken from Ensembl BioMart (release 116) as within-species paralog pairs between Ensembl genes. For each protein-coding gene, the single representative transcript and protein were taken from the MANE Select set, so that residue numbering matches the transcripts used in clinical variant reporting. Each pair of paralogs whose proteins share at least 20% identity was aligned with a global Needleman-Wunsch alignment (BLOSUM62), and the aligned residue positions were recorded. Pairs below 20% identity were not aligned, because alignments in that range are not reliable enough to transfer positions. </p> <p> Every ClinVar variant with a protein-residue consequence (missense, stop gain or loss, start loss and in-frame insertions or deletions) was assigned to the codon of the overlapping MANE Select transcript, and its reference residue was taken from the translated protein. Each variant was then projected across the alignment to the equivalent residue of every paralog, and that residue was mapped back to its genomic codon to place the feature. Variants that align to a gap, or that occur in a gene with no paralog, were not projected. The pairwise alignments themselves were converted to PSL to form the Paralog Alignments track. </p> <p> +For the domain method, the MANE Select proteins were searched against the Pfam-A +profile library (release 38.2) with HMMER, using each family's curated gathering +threshold to decide domain membership. For every domain family found in two or +more genes, the matched protein regions were aligned to the family model, and each +residue was assigned the model match-state column it occupies; this column is the +shared numbering that makes a position in one gene comparable to a position in +another. Each ClinVar coding variant that falls on a domain column was then +carried to the residue in the same column in every other gene that has the domain, +and that residue was mapped back to its genomic codon. A residue that falls +between the modeled positions of a domain, in an insertion relative to the model, +has no shared column and was not carried across. Because a few domains occur in +hundreds of genes, each variant is shown at its 25 most conserved equivalents +(residues identical to the source residue first, then chemically similar, then +different); without this limit the largest families would produce hundreds of +projections per variant. The Pfam Domains track records, for each domain instance, +the gene, the domain and the range of model columns it covers. +</p> +<p> The ClinVar data were taken from the UCSC ClinVar track for this assembly. The paralog list was downloaded from the Ensembl BioMart service at <a href="https://www.ensembl.org/biomart/martservice" target="_blank">https://www.ensembl.org/biomart/martservice</a>, and the MANE Select set from the UCSC MANE track. The commands used to build the track are documented in the <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/clinvarMapped.txt" target="_blank">makeDoc</a>, and the processing scripts are in the <a href="https://github.com/ucscGenomeBrowser/kent/tree/master/src/hg/makeDb/scripts/clinvarMapped" target="_blank">kent source tree</a>. </p> <h2>Data Access</h2> <p> The data can be explored interactively in table format with the <a href="hgTables">Table Browser</a> or the <a href="hgIntegrator">Data Integrator</a> and exported from there to spreadsheet or tab-sep tables. From scripts, the data can be accessed through our <a href="https://api.genome.ucsc.edu">API</a>, track=<i>clinvarMappedParalog</i>. </p> <p> For automated download and analysis, the annotation is stored in bigBed files that can be downloaded from <a href="http://hgdownload.soe.ucsc.edu/gbdb/hg38/clinvarMapped/" target="_blank">our download server</a>. -The files for this track are called <tt>clinvarMappedParalog.bb</tt> and -<tt>clinvarMappedParalogAln.bb</tt>. Individual regions or the whole genome annotation +The files for this track are called <tt>clinvarMappedParalog.bb</tt>, +<tt>clinvarMappedParalogAln.bb</tt>, <tt>clinvarMappedPfam.bb</tt> and +<tt>clinvarMappedPfamAln.bb</tt>. Individual regions or the whole genome annotation can be obtained using our tool <tt>bigBedToBed</tt>, which can be compiled from the source code or downloaded as a precompiled binary for your system. Instructions for downloading source code and binaries can be found <a href="http://hgdownload.soe.ucsc.edu/downloads.html#utilities_downloads">here</a>. The tool can also be used to obtain features within a given range, e.g. <tt>bigBedToBed http://hgdownload.soe.ucsc.edu/gbdb/hg38/clinvarMapped/clinvarMappedParalog.bb -chrom=chr2 -start=165000000 -end=166000000 stdout</tt>. </p> <h2>Credits</h2> <p> Thanks to Ensembl for the paralog annotations, to the MANE collaboration between -NCBI and EMBL-EBI for the reference transcript set, and to ClinVar for the variant -data. The paralogue annotation concept was developed by Ware, Walsh, Cook and -colleagues. +NCBI and EMBL-EBI for the reference transcript set, to the Pfam team at EMBL-EBI +for the protein domain models, and to ClinVar for the variant data. The paralogue +annotation concept was developed by Ware, Walsh, Cook and colleagues. </p> <h2>References</h2> <p> Ware JS, Walsh R, Cunningham F, Birney E, Cook SA. <a href="https://doi.org/10.1002/humu.22114" target="_blank"> Paralogous annotation of disease-causing variants in long QT syndrome genes</a>. <em>Hum Mutat</em>. 2012 Aug;33(8):1188-1191. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/22581653" target="_blank">22581653</a>; PMC: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640174/" target="_blank">PMC4640174</a> </p> <p> Walsh R, Peters NS, Cook SA, Ware JS. <a href="http://jmg.bmj.com/lookup/pmidlookup?view=long&pmid=24136861" target="_blank"> Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia</a>. <em>J Med Genet</em>. 2014 Jan;51(1):35-44. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/24136861" target="_blank">24136861</a>; PMC: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888601/" target="_blank">PMC3888601</a> </p> <p> Morales J, Pujar S, Loveland JE, Astashyn A, Bennett R, Berry A, Cox E, Davidson C, Ermolaeva O, Farrell CM <em>et al</em>. <a href="https://doi.org/10.1038/s41586-022-04558-8" target="_blank"> A joint NCBI and EMBL-EBI transcript set for clinical genomics and research</a>. <em>Nature</em>. 2022 Apr;604(7905):310-315. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/35388217" target="_blank">35388217</a>; PMC: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007741/" target="_blank">PMC9007741</a> </p> +<p> +Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, Tosatto SCE, Paladin L, +Raj S, Richardson LJ <em>et al</em>. +<a href="https://www.ncbi.nlm.nih.gov/pubmed/33125078" target="_blank"> +Pfam: The protein families database in 2021</a>. +<em>Nucleic Acids Res</em>. 2021 Jan 8;49(D1):D412-D419. +PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33125078" target="_blank">33125078</a>; PMC: <a +href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779014/" target="_blank">PMC7779014</a> +</p> +