fe36c1b0cd47c32282b161d2f5abd89f19b168da gperez2 Wed Jul 29 15:27:29 2026 -0700 Made updates to the hg38 MPC track Description section, Display Conventions and Configuration section (added a legend table and other edits), and Methods section. Also updated gnomadMpc.ra to unhide transcript fields on the details page, reformat the mouseOver display, and clarify the Score field's scale, refs #37478 diff --git src/hg/makeDb/trackDb/human/hg38/gnomadMpc.html src/hg/makeDb/trackDb/human/hg38/gnomadMpc.html index 0d17cd3e560..69f6390e06d 100644 --- src/hg/makeDb/trackDb/human/hg38/gnomadMpc.html +++ src/hg/makeDb/trackDb/human/hg38/gnomadMpc.html @@ -1,171 +1,208 @@ <h2>Description</h2> <p> -Missense variants change a single amino acid in a protein and are a common -source of variants of uncertain significance (VUS): about 90% of missense -variants in ClinVar are VUS. The <b>MPC</b> score ("Missense deleteriousness -Prediction by Constraint") is a machine-learning score that flags missense -variants likely to be deleterious by combining three lines of evidence: -(i) regional missense constraint (how depleted the surrounding sub-genic -region is of rare missense variation in the general population), (ii) the -biochemical severity of the specific amino-acid substitution as captured by -PolyPhen-2, and (iii) cross-species conservation (phyloP). The model is -trained to separate pathogenic from benign missense variation under strong -heterozygous selection; higher scores indicate greater predicted -deleteriousness. The authors report that MPC ≥ 2.5 is strongly -enriched for de novo variants in individuals with severe developmental -disorders relative to their unaffected siblings, with MPC 2–2.5 showing -intermediate enrichment and MPC < 2 little enrichment. +This track shows MPC v4.1.1 ("Missense deleteriousness Prediction by +Constraint"), a machine-learning score that predicts which missense variants +are likely to be deleterious. It was computed by the Broad Institute gnomAD +team from the <b>gnomAD v4.1.1</b> release of 730,947 exomes aligned to +GRCh38/hg38. Scores are provided for every possible single-nucleotide +missense variant in 17,841 MANE Select or canonical protein-coding +transcripts that passed gnomAD QC, as well as for an additional 1,534 +transcripts that failed QC (the authors note that scores may be less +accurate in these 1,534 transcripts). </p> <p> -This track shows MPC v4.1.1, computed by the Broad Institute gnomAD team from -the <b>gnomAD v4.1.1</b> release of 730,947 exomes aligned to GRCh38. Scores -are provided for every possible single-nucleotide missense variant in 17,841 -MANE Select or canonical protein-coding transcripts that passed gnomAD QC, as -well as for an additional 1,534 transcripts that failed QC (the authors note -that scores may be less accurate in the latter). Our MPC track on hg19 -is an older release of the MPC score, calculated on gnomAD v2 (125,748 exomes) rather -than gnomAD v4 (730,947 exomes). +Missense variants change a single amino acid in a protein and are a common +source of variants of uncertain significance (VUS): about 90% of missense +variants in ClinVar are VUS. MPC predicts which missense variants are likely +deleterious by combining three lines of evidence: (i) regional missense constraint (how +depleted the surrounding sub-genic region is of rare missense variation in +the general population), (ii) the biochemical severity of the specific +amino-acid substitution and additional protein-structure and homology +information from PolyPhen-2, and (iii) cross-species conservation (phyloP). +Higher scores indicate greater predicted deleteriousness. </p> -<h2>Display Conventions and Configuration</h2> <p> -Two views of the same underlying data are available: +This data is available as two separate tracks: </p> <ul> -<li><b>gnomAD MPC</b> — four bigWig subtracks, one for each possible -alternate allele (A, C, G, T). At a given genomic position, the subtrack for -a given alternate allele shows the MPC score for the substitution from the -reference base to that alternate base. Positions where the alternate base -equals the reference base, or where no MPC score is available (for example, -outside coding regions), are drawn as 0. Scores range from 0 to 6, where 6 is -the ceiling assigned when a variant is more severe than every benign variant -in the MPC training set (the maximum real computed value is just over 5); -the track's default view limit is 0–3 because the vast majority of -variants score below 3. Mouseover shows the score. When a variant is -annotated against more than one transcript, the four bigWigs show the -<b>maximum</b> (most deleterious) MPC across transcripts.</li> -<li><b>gnomAD MPC overlaps</b> — a bigBed track restricted to the small +<li><b>gnomAD MPC</b> is a set of four bigWig subtracks, one for each +possible alternate allele (A, C, G, T), with scores ranging from 0 to 6. +At a given genomic position, the subtrack for a given alternate allele +shows the MPC score for the substitution from the reference base to that +allele. A score of 6 is the ceiling assigned when a variant is more severe +than every benign variant in the MPC training set (the maximum real +computed value is just over 5). When a variant is scored against more +than one transcript, the four bigWigs show the <b>maximum</b> (most +deleterious) MPC across transcripts.</li> +<li><b>gnomAD MPC overlaps</b> is a bigBed track covering the small subset of variants that are scored against more than one transcript (about -250,000, or 0.4% of the ~70 million scored variants). Each row carries the -full list of Ensembl transcripts scoring that variant together with their -individual MPC scores on the details page. Single-transcript variants are -not included in this track because the bigWig view already fully represents -them. A range filter on <tt>mpcMax</tt> is available from the track -configuration page. Items are colored by max MPC (gray < 1, -orange 1–3, red ≥ 3). Use this view to inspect transcripts whose -MPC scores disagree for the same underlying variant.</li> +250,000, or 0.4% of the ~70 million scored variants). Each item lists the +Ensembl transcripts and their individual MPC scores for that variant on +the details page, showing which transcripts' scores differ. Different +transcripts overlapping the same position don't always have an MPC score +for the same alternate alleles. Single-transcript variants are not +included in this track because the bigWig track already fully represents +them.</li> </ul> + <p> -Across the 250,000 multi-transcript variants, per-transcript MPC scores -typically agree within 0.5 units; only a few percent differ by more than -0.5. The bigBed view is the authoritative source for the full -transcript-level detail in those cases; the bigWig view collapses -transcripts by showing the maximum MPC at each position. +The <a href="../cgi-bin/hgTrackUi?db=hg19&g=gnomadMpc">MPC track on hg19</a> +is an older release of the MPC score, calculated on gnomAD v2 (125,748 +exomes) rather than gnomAD v4 (730,947 exomes). </p> +<h2>Display Conventions and Configuration</h2> +<ul> +<li><b>gnomAD MPC</b>: Each subtrack has a fixed color from the viridis +palette: A is purple, C is blue, G is teal, T is yellow. At a given +position, the subtrack matching the reference base shows 0, since that +isn't a real substitution. Positions outside the scored transcripts (for +example, outside coding regions) have no data. The track's default view +limit is 0–3 because the vast majority of variants score below 3. +Mouseover shows the score.</li> +<li><b>gnomAD MPC overlaps</b>: A range filter on <tt>mpcMax</tt> is +available from the track configuration page. Items are colored by max MPC: +<table> + <thead> + <tr> + <th style="border-bottom: 2px solid #6678B1;">Color</th> + <th style="border-bottom: 2px solid #6678B1;">Max MPC range</th> + </tr> + </thead> + <tr> + <th bgcolor="#C8C8C8"></th> + <th align="left">< 1</th> + </tr> + <tr> + <th bgcolor="#FFC864"></th> + <th align="left">1 – 2</th> + </tr> + <tr> + <th bgcolor="#FF9632"></th> + <th align="left">2 – 3</th> + </tr> + <tr> + <th bgcolor="#C80000"></th> + <th align="left">≥ 3</th> + </tr> +</table> +Mouseover shows the variant, its max MPC score, and the number of +transcripts that scored it.</li> +</ul> + <h2>Methods</h2> +<h3>Regional missense constraint (MCR)</h3> <p> -<b>Regional missense constraint (MCR).</b> For each of 17,841 QC-passing +For each of 17,841 QC-passing MANE Select or canonical coding transcripts, the authors tallied the observed rare missense variants (allele count > 0, allele frequency < 0.1%, %AN ≥ 20, QC PASS) in gnomAD v4.1.1 against the expected count under a position- and coverage-adjusted mutational model. A recursive likelihood-ratio test (Poisson model, p-value threshold 0.001, minimum 16 expected missense variants per sub-region) identifies change-points at which the transcript-wide observed/expected (OE) ratio deviates significantly; each resulting segment is a missense constraint region (MCR). 36% of transcripts (6,361/17,841) harbor two or more MCRs. MCR missense OE was calibrated against ClinVar P/LP vs. B/LB missense variants following ClinGen recommendations for the ACMG/AMP guidelines: OE ≤ 0.36 meets <i>moderate</i> evidence for pathogenicity, OE ≤ 0.59 meets <i>supporting</i> evidence for pathogenicity, OE > 0.97 and OE > 1.23 meet supporting and moderate evidence for benignity, respectively. </p> +<h3>MPC score</h3> <p> -<b>MPC score.</b> MPC is an XGBoost gradient-boosted-tree classifier that +MPC is an XGBoost gradient-boosted-tree classifier that takes as input (1) MCR missense OE, (2) gene-level constraint, (3) a per-substitution amino-acid severity feature, (4) the PolyPhen-2 -pathogenicity score, and (5) phyloP conservation. Training: 20,931 +pathogenicity score, and (5) phyloP conservation. The model is trained to +distinguish pathogenic missense variants under strong heterozygous +selection from benign missense variants under neutral to near-neutral +selection. Training: 20,931 "pathogenic" variants (high-quality ClinVar P/LP in 2,987 haploinsufficient genes with pHaplo ≥ 0.86 or in 359 non-LoF DD genes from Gene2Phenotype) vs. 93,638 "benign" variants (high-quality ClinVar B/LB or gnomAD variants with AF > 0.1% in the same gene set). The model is applied to all 70,313,598 possible exome-wide missense variants in the Ensembl VEP table. For a variant <i>i</i>, MPC is <i>d</i><sub><i>i</i></sub> = log<sub>10</sub>(<i>M</i> / <i>m</i><sub><i>i</i></sub>), where <i>M</i> is the number of benign training variants and <i>m</i><sub><i>i</i></sub> is the number of those with a fitted pathogenicity probability lower than variant <i>i</i>'s; when -<i>m</i><sub><i>i</i></sub> is 0 the score is capped at 6. Higher scores -indicate greater predicted deleteriousness. The authors caution that MPC is +<i>m</i><sub><i>i</i></sub> is 0 the score is capped at 6. Restricted to genes already +known to cause developmental disorders, the authors report that de novo +variants with MPC ≥ 2.5 are strongly enriched in affected individuals +relative to their unaffected siblings, with MPC 2–2.5 showing +intermediate enrichment and MPC < 2 little enrichment. The authors +caution that MPC is best suited to modelling strong fitness effects (as expected given its training set) and that naively taking the maximum of MPC and AlphaMissense <i>decreases</i> case/control discrimination for de novo variants relative to either score alone. Code for calculating the MPC scores and MCRs is available at the <a href="https://github.com/broadinstitute/regional_missense_constraint" target="_blank">broadinstitute/regional_missense_constraint</a> GitHub repository. </p> +<h3>UCSC Methods</h3> <p> -<b>At UCSC.</b> The precomputed MPC score table was downloaded from the +The precomputed MPC score table was downloaded from the gnomAD Broad public bucket at -<a href="https://storage.googleapis.com/gcp-public-data--gnomad/papers/2026-rmc/gnomad_v4.1.1_mpc.tsv.bgz">gs://gcp-public-data--gnomad/papers/2026-rmc/gnomad_v4.1.1_mpc.tsv.bgz</a>, +<a href="https://storage.googleapis.com/gcp-public-data--gnomad/papers/2026-rmc/gnomad_v4.1.1_mpc.tsv.bgz" target="_blank">gs://gcp-public-data--gnomad/papers/2026-rmc/gnomad_v4.1.1_mpc.tsv.bgz</a>, companion to the Hail-table release <tt>gnomad_v4.1.1_mpc.ht</tt> in the same directory. The input TSV contains one row per (locus, alleles, transcript) combination, for 70M rows. -Two Python scripts in <a target="_blank" -href="https://github.com/ucscGenomeBrowser/kent/tree/master/src/hg/makeDb/scripts/gnomadMpc">src/hg/makeDb/scripts/gnomadMpc</a> -convert to bigWig/bigBed formats. Build commands are documented -in the +href="https://github.com/ucscGenomeBrowser/kent/tree/master/src/hg/makeDb/scripts/gnomadMpc">Two Python scripts</a> +convert to bigWig/bigBed formats, available on GitHub. Build commands are +documented in the <a target="_blank" -href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/gnomadMpc.txt">hg38/gnomadMpc.txt</a> +href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/gnomadMpc.txt">gnomadMpc.txt</a> makeDoc file. </p> <h2>Data Access</h2> <p> The raw data can be explored interactively with the <a href="../cgi-bin/hgTables">Table Browser</a> or the <a href="../cgi-bin/hgIntegrator">Data Integrator</a>. For automated access, this track is available via our <a href="../goldenPath/help/api.html">API</a>. The underlying bigWig and bigBed files are at <a href="http://hgdownload.soe.ucsc.edu/gbdb/hg38/gnomAD/mpc/" target="_blank">our download server</a> as <tt>a.bw</tt>, <tt>c.bw</tt>, <tt>g.bw</tt>, <tt>t.bw</tt>, and <tt>mpcOverlaps.bb</tt>. Individual positions or whole chromosomes can be extracted with <tt>bigWigToBedGraph</tt> / <tt>bigWigToWig</tt> (for the bigWigs) or <tt>bigBedToBed</tt> (for the bigBed), for example: </p> <pre> bigWigToBedGraph -chrom=chr1 -start=100000 -end=100500 \ http://hgdownload.soe.ucsc.edu/gbdb/hg38/gnomAD/mpc/a.bw stdout </pre> <p> The original MPC table and the accompanying missense constraint regions can be downloaded from the <a href="https://gnomad.broadinstitute.org/downloads" target="_blank">gnomAD downloads page</a>. </p> <h2>Credits</h2> <p> Thanks to the gnomAD production team and the Samocha and MacArthur laboratories for generating and releasing the MPC scores. </p> <h2>References</h2> <p> Wang L, Chao KR, Panchal R, Liao C, Abderrazzaq H, Ye R, Schultz P, Compitello J, Grant RH, Kosmicki JA, Weisburd B, Phu W, Wilson MW, Laricchia KM, Goodrich JK, Goldstein D, Goldstein JI, Vittal C, Poterba T, Baxter S, Watts NA, Solomonson M, gnomAD consortium, Tiao G, Rehm HL, Neale BM, Talkowski ME, MacArthur DG, O'Donnell-Luria A, Karczewski KJ, Radivojac P, Daly MJ, Samocha KE. <a href="https://doi.org/10.1101/2024.04.11.588920" target="_blank">The landscape of regional missense mutational intolerance quantified from 730,947 exomes</a>. <em>bioRxiv</em> April 23, 2026; doi: <a href="https://doi.org/10.1101/2024.04.11.588920" target="_blank">10.1101/2024.04.11.588920</a>. </p>