614ca430db1c23f496ccc5655d27b469e1c53443 lrnassar Fri Jul 31 16:38:30 2026 -0700 Apply Cardiomyopathy VCEP feedback: BP7 splice-only, drop PS4 tracks, evidence-first Variant Evidence Summary. refs #37446 Per the CM VCEP's answers to the interpretation questions: - BP7: remove the conservation (phyloP) requirement and set the SpliceAI cutoff to < 0.1, per Walker 2023 (PMID 37352859). - PS4: remove the Walsh 2017 gene-level OR and Atlas EF display tracks (the VCEP computes PS4 from current cohorts). Scripts and data are retained in the tree; the tracks are dropped from the hub trackDb. - Rename the former provisional/computable-codes track to "Variant Evidence Summary" and switch its mouseover to an evidence-first layout: each item leads with the data and is tagged with the ACMG criterion it would support; no overall classification is computed. - Confirmed and reflected in the docs: EvRepo is the PS1/PM5 reference (Q1); the PM4 last-exon / within-50-nt rule (Q2); CardioBoost stays informational (Q6); the PM1 codon ranges are HCM-only (Q8); no functional-score dataset is currently VCEP-approved (Q4). diff --git src/hg/makeDb/doc/Cardiomyopathy.txt src/hg/makeDb/doc/Cardiomyopathy.txt index d55bf901d20..2fdcad99aa9 100644 --- src/hg/makeDb/doc/Cardiomyopathy.txt +++ src/hg/makeDb/doc/Cardiomyopathy.txt @@ -14,31 +14,33 @@ # GN101 ACTC1 v1.0.0 HCM (AD) # GN102 MYL2 v1.0.0 HCM (AD) # GN103 MYL3 v1.0.0 HCM (AD) # # ARVC genes are out of scope (separate ClinGen panel, affiliation 40003). # # Expert contacts: # Lucas Bronicki, PhD, FACMG — Cardiomyopathy VCEP Chair # Haley Garrett, MPH — Coordinator (Haley_Garrett@med.unc.edu) # ClinVar submitter ID: 506161 ("ClinGen Cardiomyopathy Variant # Curation Expert Panel") # # Calibration sources: # Walsh 2017 (PMID 27532257; Genet Med; DOI 10.1038/gim.2016.90) # — PS4 case-control reference (Tables S5A/S5B; -# 60,706 ExAC samples; 7,855 cases) +# 60,706 ExAC samples; 7,855 cases). NOTE: the +# Walsh-2017 PS4 track was RETIRED from the hub +# 2026-07 per the VCEP (Q5). # Walsh 2019 (PMID 30696458; Genome Medicine; DOI 10.1186/s13073-019-0616-z) # — PM1 hotspot codon ranges (Table S4), # per-gene NonTrunc ExAC denominators # (Table S1), and 155 pre-EvRepo per-variant # curations (Table S6) # # MANE Select transcripts (verified against /gbdb/hg38/mane/mane.bb): # MYH7 NM_000257.4 NP_000248.2 chr14 (-) # MYBPC3 NM_000256.3 NP_000247.2 chr11 (-) # TNNT2 NM_001276345.2 NP_001263274.1 chr1 (-) # TNNI3 NM_000363.5 NP_000354.4 chr19 (-) # TPM1 NM_001018005.2 NP_001018005.1 chr15 (+) ← only plus-strand gene # ACTC1 NM_005159.5 NP_005150.1 chr15 (-) # MYL2 NM_000432.4 NP_000423.2 chr12 (-) # MYL3 NM_000258.3 NP_000249.1 chr3 (-) @@ -60,34 +62,34 @@ # hub.txt, genomes.txt # hg38/trackDb.txt, hg19/trackDb.txt # cardiomyopathy.html (shared description page) # cmp_downloads/ (source data — checked at A.0 + cached) # scripts_local_copy/ (insurance copy of all 12 build scripts; # live copy is at ~/kent/...) # cmpVCEPClinDomains/ (PM1 hotspot regions) # cmpVCEPPVS1/ (MYBPC3-only PVS1 caveats) # cmpVCEPAFfrequencies/ (gnomAD v4.1 BA1/BS1/PM2_supporting) # cmpVCEPAnnotate/ (hgVai consequence + HGVSp annotation TSV) # cmpVCEPRevel/ (REVEL PP3/BP4) # cmpVCEPCardioBoost/ (CardioBoost missense predictor — off) # cmpVCEPEvRepo/ (VCEP Curated Variants — EvRepo, with codes) # cmpVCEPClinVar506161/ (VCEP ClinVar submissions, no codes) # cmpVCEPWalsh2019/ (Walsh 2019 Pre-EvRepo Table S6 curations) -# cmpVCEPWalshOR/ (Walsh 2017 gene-level OR — PS4) +# cmpVCEPWalshOR/ (Walsh 2017 gene-level OR — PS4; RETIRED from hub, Q5) # cmpVCEPAtlasEF/ (Atlas of Cardiac Genetic Variation -# per-variant + UCSC-computed OR — PS4) -# cmpVCEPProvisionalClass/ (Computable ACMG Criteria Summary; per-variant codes) +# per-variant + UCSC OR — PS4; RETIRED from hub, Q5) +# cmpVCEPProvisionalClass/ (Variant Evidence Summary; per-variant evidence + criteria) # # Build scripts: ~/kent/src/hg/makeDb/scripts/cardiomyopathyVCEP/ # cmpVCEPClinDomains.py (B.1 — PM1 hotspot regions; also provides # parse_mane_record, cds_exons, # aa_to_genomic_segments helpers imported # by B.2, B.6, B.9, B.11) # cmpVCEPPVS1.py (B.2) # cmpVCEPAFfrequencies.py (B.3; fetch_gene_variants() defines the # shared variant universe reused by B.6/B.11) # cmpVCEPAnnotate.py (B.6 — hgVai consequence/HGVSp annotation) # cmpVCEPRevel.py (B.4) # cmpVCEPCardioBoost.py (B.5) # cmpVCEPEvRepo.py (B.7) # cmpVCEPWalsh2019.py (B.7c) # cmpVCEPClinVar506161.py (B.8) @@ -148,32 +150,32 @@ # TNNT2 89-189 (MANE NM_001276345.2; classic NM_001001430.2 = 79-179) # TNNI3 141-209 # (TPM1, ACTC1, MYL2, MYL3 — no PM1 region defined) # MYBPC3 PVS1 caveats: # NMD-escape boundary: codon 1254+ # Micro-exons: 10, 11, 14 # In-frame exons: 2, 3, 4, 8, 9, 10, 11, 14, 20, 22, 24, 25, 26, 27 # # CSpec points where the spec is silent / leaves a curator choice (provisional # decisions made for the build; posed to the VCEP for confirmation): # - PS1/PM5 reference DB of "established pathogenic" (spec says "per # Richards 2015", names none) — build uses VCEP EvRepo P/LP, leave-one-out. # - PM4 for MYH7 (PVS1 N/A): spec redirects PM4 to non-NMD truncating at # Moderate/Supporting, no boundary given — build uses last exon OR within # 50 nt of the final exon-exon junction. -# - BP7 "not highly conserved": no metric/cutoff in spec — build uses -# phyloP470way <= 0 together with SpliceAI < 0.20. +# - BP7 "not highly conserved": the VCEP removed the conservation requirement +# and set BP7 at SpliceAI < 0.1 (Walker 2023, PMID 37352859). # # # A.2 ClinGen EvRepo classifications (REST JSON) # # curl -fsSL 'https://erepo.genome.network/evrepo/api/classifications?expertpanel=Cardiomyopathy+VCEP&format=json' \ # -o cmp_downloads/erepo/cardiomyopathyVCEP_classifications.json # # State at 2026-06-29 refresh: 25 variants (all MYH7). One change vs the # April pull — CAR:CA016422 moved Likely Pathogenic -> Uncertain Significance. # April JSON retained as *.april2026.json.bak. # # # A.3 ClinVar submitter 506161 (filter from weekly VCV release) # # Precise column-10 match against the submission_summary (loose grep over- @@ -186,31 +188,31 @@ # expert panel". Classifications: 33 P + 32 LP + 75 VUS + 9 LB + 50 B = 199. # # # A.4 gnomAD v4.1 exomes (already on hgwdev; no download) # /hive/data/outside/gnomAD.4/v4.1/exomes/gnomad.exomes.v4.1.sites.chr{N}.vcf.bgz # Field used: fafmax_faf95_max (max FAF95 across genetic ancestry groups), # queried per-region via tabix. # Public mirror: https://hgdownload.soe.ucsc.edu/gbdb/hg38/gnomAD/v4.1/exomes/exomes.bb # # A.5 REVEL (already on hgwdev; no download) # /gbdb/hg38/revel/{a,c,g,t}.bw (per-alt-nucleotide bigwigs) # Public mirror: https://hgdownload.soe.ucsc.edu/gbdb/hg38/revel/ # # A.6 SpliceAI (already on hgwdev; no download) # /gbdb/hg38/bbi/spliceAi.bb (bed9+4; AIscore in col 9, name="ref>alt") -# Used by the B.11 SpliceAI safety net and BP7. +# Used by the B.11 splice flag and BP7 (SpliceAI < 0.1). # # A.7 CardioBoost precomputed predictions # cmp_downloads/cardioboost/cm_prediction.RData (precomputed table, # ~65k rows; ~31k in our 8 genes — NOT just model objects) # Source: https://github.com/ImperialCardioGenetics/CardioBoost_manuscript # Loaded via /usr/bin/Rscript (the team Rscript is broken on hgwdev — # missing libgfortran.so.3). Coordinates are GRCh37 with numeric chrom # names; B.5 adds the chr prefix and liftOvers to hg38. # # A.8 Walsh PS4 + PM1 calibration supplements # mkdir -p cmp_downloads/walsh ; cd cmp_downloads/walsh # # Walsh 2017 (PS4 case-control) — Springer direct (avoids PMC PoW challenge) # curl -fsSL -o walsh2017_supplement.zip \ # "https://static-content.springer.com/esm/art%3A10.1038%2Fgim.2016.90/MediaObjects/41436_2017_BFgim201690_MOESM9_ESM.zip" # unzip -o walsh2017_supplement.zip # -> Supplementary_Tables_resubmit.xlsx @@ -314,122 +316,127 @@ # are rendered: the 32 previously unmatched-to-ClinVar entries (complex # indels + 4 TNNT2 SNVs incl. R92W) are placed via walsh_coords_via_tool() # = hgvsToVcf on each gene's Walsh-paper transcript, gated on FILTER==PASS. # TNNT2 uses NM_001001430.2 (MANE gives HgvsRefAssertedMismatch); TNNT2 hg19 # coords via liftOver from hg38. 27 variants tagged "Walsh-upgraded" (the new # PM1 EF rule, asterisked in Table S6). Classification strings normalized to # "Uncertain Significance" (not "VUS"). Standard ACMG ramp. # # B.8 cmpVCEPClinVar506161.py — VCEP ClinVar submissions (Final, no codes) # Output: 199 features. Joined to variant_summary for hg38 + hg19 coords. # All carry review status "reviewed by expert panel". 25 of 199 overlap # EvRepo (flagged inline in the mouseover). Standard 5-tier ACMG ramp (the # earlier desaturated palette was dropped). Carries no per-code evidence. # # B.9 cmpVCEPWalshOR.py — Walsh 2017 gene-level case-control OR (PS4) +# [RETIRED from the hub 2026-07 per the VCEP (Q5: do not display Walsh 2017/2019 +# PS4; ORs use current cohorts). Script + data retained in the tree for reference.] # Source: Walsh 2017 Supplementary_Tables_resubmit.xlsx, Tables S5A (HCM) / # S5B (DCM). Output: 48 features = 8 genes x {HCM, DCM} x {All protein- # altering, Truncating, Non-truncating}, each spanning the gene CDS (MANE), # filterable by gene / cohortDisease / variantClass / ps4Strength. # PS4 strength by OR 95%-CI lower bound (Strong >=20, Moderate >=10, # Supporting >=5, else below threshold): Strong 1, Moderate 7, Supporting 9, # below threshold 31. Standout: MYBPC3 truncating-HCM OR 118.8 (86.1-163.9) # -> Strong. hg38 from MANE CDS; hg19 via liftOver. Replaces the earlier # Walsh-2019 EF table (a different statistic; per CSpec, PS4 cites Walsh 2017). # # B.10 cmpVCEPAtlasEF.py — Atlas per-variant case-counts + UCSC-computed OR (PS4) +# [RETIRED from the hub 2026-07 per the VCEP (Q5). Script + data retained.] # Source: cmp_downloads/atlas/variants/var_*.html (173 parsed; 16 parse # failures). Output: 178 features (a variant renders once per disease cohort # where it has data). UCSC computes the OR (Fisher 2x2 with Haldane 0.5 # correction; Woolf log-OR 95% CI) from Atlas case counts against ExAC # controls; per-gene Walsh-2019 NonTrunc ExAC denominators are used for # non-truncating vartypes, else the 60,706 baseline. PS4 strength binning: # Strong 16, Moderate 30, Supporting 44, below threshold 88. Every mouseover # carries the caveat that the OR is UCSC-computed against ExAC (not gnomAD). # -# B.11 cmpVCEPProvisionalClass.py — Computable ACMG Criteria Summary -# (Formerly "NON-FINAL Provisional Classification"; reframed 2026-07-08 per -# the CM VCEP chair L. Bronicki. The track no longer computes an overall ACMG -# classification, only the computable codes that fire per variant.) +# B.11 cmpVCEPProvisionalClass.py — Variant Evidence Summary +# (Formerly "NON-FINAL Provisional Classification"; reframed 2026-07 per the +# CM VCEP. Computes no overall classification. For each variant it lists, +# evidence-first, the computable evidence and the ACMG criterion each item +# would support.) # Variant universe: identical to B.3 (10,974). Consumes the B.6 annotation -# TSV. Computable codes applied: BA1/BS1/PM2_supporting (B.3 FAF95), +# TSV. Evidence gathered: BA1/BS1/PM2_supporting (B.3 FAF95), # PP3/BP4 (REVEL, missense), PM1 (CSpec hotspot region), PS1/PM5 (EvRepo # P/LP reference, leave-one-out; a variant cannot earn the code from its # own entry; PS1 reference excludes established splice-impact variants e.g. # MYBPC3 c.2308G>A), PM4 (NMD-escaping truncating, non-MYBPC3: last exon or # within 50 nt of the final exon-exon junction), BP7 (synonymous + -# SpliceAI < 0.20 + phyloP470way <= 0). PM1<->PM5 mutual exclusion enforced -# per CSpec (keep PM5, the variant-specific code; drop PM1; PM1+PS1 -# co-occurrence flagged). HCM/DCM diseaseTag populated. A SpliceAI score -# >= 0.20 is recorded as an informational splice flag. -# Per-variant output = the list of triggered codes only; NO overall +# SpliceAI < 0.1, per Walker 2023 PMID 37352859; conservation requirement +# removed per the VCEP). PM1<->PM5 mutual exclusion enforced per CSpec (keep +# PM5, the variant-specific code; drop PM1; PM1+PS1 co-occurrence flagged). +# HCM/DCM diseaseTag populated. A SpliceAI score >= 0.20 is recorded as an +# informational splice flag. +# Mouseover is evidence-first ("evidence -> supports CODE"); NO overall # classification is calculated. The GN002 combining logic remains in the # script as classify() but is retired/uncalled. Clinical/functional codes # (PS2/PS3/PS4/PP1/PP4/BS3/BS4) are not computed. Single neutral display # color 91,107,122; no classification encoded. -# Output: 10,974 features. Code firing: BA1 210, BS1 367, PM2_Supporting -# 9,893, PP3 1,436, BP4 1,647, BP7 1,356, PM1 1,293, PM4 27, PM5 11, PS1 0. +# Output: 10,974 features. Evidence firing: BA1 210, BS1 367, PM2_Supporting +# 9,893, PP3 1,436, BP4 1,647, BP7 2,419, PM1 1,293, PM4 27, PM5 11, PS1 0. ############################################################################## # Phase C: Hub assembly ############################################################################## # # Files written/maintained by hand (NOT generated by the build scripts): # hub.txt, genomes.txt # cardiomyopathy.html (shared description page; hub descriptionUrl) # hg38/trackDb.txt # hg19/trackDb.txt (mirrors hg38; differs in bigDataUrl + an hg19 # provenance header noting liftOver-derived coords) # -# trackDb structure: 7 top-level groups -> 11 tracks. Three are composites: -# Bioinformatic (REVEL on + CardioBoost off), VCEP Curated Variants (EvRepo on -# + ClinVar off + Walsh 2019 off), PS4 Case-Control (Walsh OR on + Atlas EF off). +# trackDb structure: 6 top-level groups -> 9 tracks. Two are composites: +# Bioinformatic (REVEL on + CardioBoost off) and VCEP Curated Variants (EvRepo on +# + ClinVar off + Walsh 2019 off). (The PS4 Case-Control composite was retired +# from the hub per the VCEP, 2026-07.) # bigBed filterValues on the ACMG-code / ps4Strength fields; default visibility # tuned so the first view is clean (dense for the big per-variant tracks). # # Validation: # hubCheck https://hgwdev.gi.ucsc.edu/~lrnassar/track_hubs/cardiomyopathyVCEP/hub.txt # # Web access (sandbox; working dir served directly via symlink): # ln -sf /hive/users/lrnassar/claude/RM37446 \ # /cluster/home/lrnassar/public_html/track_hubs/cardiomyopathyVCEP # Hub URL: https://hgwdev.gi.ucsc.edu/~lrnassar/track_hubs/cardiomyopathyVCEP/hub.txt ############################################################################## # Phase D: Verification ############################################################################## # # (Build verification only. QA history, audit findings, and review/release # readiness are tracked in Redmine #37446, not here.) # # - hubCheck: silent pass (exit 0) on hg38 + hg19. # - Cross-assembly parity (hg38 == hg19 feature counts): # PM1 28 | PVS1 16 | AF 10,974 | REVEL 22,466 | EvRepo 25 | Walsh2019 155 | -# ClinVar 199 | WalshOR 48 | AtlasEF 178 | Computable codes 10,974 | -# CardioBoost 31,236 +# ClinVar 199 | Variant evidence 10,974 | CardioBoost 31,236 # - Worked example, MYH7 p.Arg870His (NM_000257.4:c.2609G>A, chr14:23424839 hg38): # EvRepo: Pathogenic, codes PM1;PM2;PP1_Strong;PS4 # EvRepo R870C: Likely Pathogenic at the adjacent codon-870 position # (the PS1/PM5 partner) # PM1: within MYH7 167-931 # REVEL: 0.853 -> PP3_supporting # gnomAD AF: absent from v4.1 exomes -> PM2_supporting -# Walsh OR: MYH7 non-truncating HCM, OR 12.0 (10.9-13.3) -> Moderate -# Computable codes: PM1+PM2+PP3 triggered; no overall classification is -# computed (the VCEP Pathogenic call rests on PS4+PP1, manual) +# Variant evidence: PM1 hotspot, PM2 rarity, PP3/REVEL shown (each tagged with +# the criterion it supports); no overall classification (the VCEP +# Pathogenic call rests on PS4+PP1, manual) ############################################################################## # Phase E: Otto cron (TODO — gated on VCEP sign-off; do AFTER deployment) ############################################################################## # # DO NOT enable until the VCEP signs off (Phase F gate). The weekly refresh # touches EvRepo + ClinVar 506161 only; premature activation could surface # unreviewed VCEP curations on the public hub. # # Mirror the TP53 pattern at /hive/data/outside/otto/cardiomyopathyVCEP/ # (doUpdate.sh + checkCMPVCEPClinVar.sh). Crontab (NOT activated until sign-off): # # Cardiomyopathy VCEP weekly EvRepo + ClinVar update # 2x 03 * * 2 umask 002; /hive/data/outside/otto/cardiomyopathyVCEP/doUpdate.sh # Tuesday ~03:2x UTC — offset a few minutes from TP53 (03:15) and InSiGHT (03:10).