1478a90404ea80636ae160b7b150fcaa34d80b50 lrnassar Tue Aug 18 15:14:02 2026 -0700 Adding Zanti et al 2025 case-control LRs to the ENIGMA BRCA1/BRCA2 PP4/BP5 track. refs #37886 New BRCAmlaZanti.py rebuilds the BRCAmla track with the case-control likelihood ratios from Zanti et al. 2025 (PMID 40413188) replacing the 20-variant iCOGS case-control component from Parsons et al. 2019, which overlaps the Zanti cohorts. Track grows from 4,436 to 13,481 variants per assembly, with new per-cohort columns (BRIDGES, CARRIERS, UK Biobank). Makedoc documents the build and release steps. Approach and combined-LR caveats reviewed with the ENIGMA collaborators on the ticket. diff --git src/hg/makeDb/doc/enigma.txt src/hg/makeDb/doc/enigma.txt index 5b879f4899a..9766849413f 100644 --- src/hg/makeDb/doc/enigma.txt +++ src/hg/makeDb/doc/enigma.txt @@ -1,62 +1,104 @@ #RM#32919 mkdir /hive/data/inside/enigmaTracksData # excel data provided by Anna on RM and converted to txt and uploaded to directory for all tracks mkdir /gbdb/hg38/bbi/enigma mkdir /gbdb/hg19/bbi/enigma #The 5 tracks were then created by individual scripts that can all be found in the following directory: ~/kent/src/hg/makeDb/scripts/enigma/ #Quick link for github: https://github.com/ucscGenomeBrowser/kent/tree/master/src/hg/makeDb/scripts/enigma ############################################################################# # Update to CSpec specification v1.2 (2026-08-17) RM #38130 # ClinGen released v1.2 of the ENIGMA BRCA1/BRCA2 specifications (approved # 2025-01-09): BRCA1 GN092 (doi 10.5281/zenodo.21434315), BRCA2 GN097 # (doi 10.5281/zenodo.21434343). Comparison against the v1.1 tables showed data # changes only in Table 4 (splice-site PVS1 codes) and Table 9 (PMIDs and typo # fixes); ST1 exon weights and the clinical domain definitions are unchanged, so # only BRCAsplicing and BRCAfunctionalAssays were rebuilt. BRCAmla is built from # publications and is independent of the specification version. mkdir /hive/data/inside/enigmaTracksData/v1.2 # Source files downloaded from the CSpec registry "Files & Images" panel # (https://cspec.genome.network/cspec/ui/svi/doc/GN092): # Table 4: https://cspec.genome.network/cspec/File/id/ca5cf57b-94df-4ad6-a001-c62ceccb3845/data # Table 9: https://cspec.genome.network/cspec/File/id/0a35d6a8-5050-44b6-8a9d-babe8cdc06b2/data # SuppTbls: https://cspec.genome.network/cspec/File/id/cb4a09fe-30f4-4aa8-9d76-d7ea407c9754/data # Spec doc: https://cspec.genome.network/cspec/File/id/11e62fec-23b0-4a3e-b2df-751855301746/data # saved as CSpec_BRCA12ACMG_Rules-Specifications_V1.2_Table-4.xlsx etc. # Export the needed sheets to text. Merged cells are expanded; the Table 9 # banner row v1.2 inserted is dropped so the layout matches the v1.1 export. # The new "Dace & Findlay, Interim Report" sheet in the Table 9 xlsx holds # interim (uncalibrated) results and is intentionally not used. python3 ~/kent/src/hg/makeDb/scripts/enigma/exportV12Sheets.py # The v1.2 Table 4 excel is a visual per-exon layout, unlike the flat table used # for v1.1, so a converter rebuilds the flat 8-column format the track script # consumes. Exons split by the NMD-escape boundary are encoded in v1.2 as # PTCp.Y qualifiers; the converter turns those back into the c. sub- # ranges used in v1.1. Text is kept as UTF-8 (v1.1 text had mangled the Greek # delta to "?"). python3 ~/kent/src/hg/makeDb/scripts/enigma/convertTable4toFlat.py # Rebuild the two tracks. Both scripts now write into the v1.2/ dir; the hub and # the /gbdb symlinks keep pointing at the fixed filenames one level up, which are # only overwritten at release (below). The two haplotype variants in Table 9 # (c.[5359T>A;5363G>A] and c.[1073T>G;1078T>C;1084G>C;1086G>T]) cannot be # converted by hgvsToVcf and are skipped, same as in the v1.1 build. python3 ~/kent/src/hg/makeDb/scripts/enigma/BRCAfunctionalAssays.py python3 ~/kent/src/hg/makeDb/scripts/enigma/BRCAsplicing.py # Release: copy the verified .bb files onto the staging filenames the symlink # chain serves (do NOT touch the symlinks themselves), then copy the updated # hub.txt, trackDb.txt, enigma.html and the v1.2 raw files into # /hive/data/outside/enigma/ (= htdocs-hgdownload/hubs/enigma). # for db in Hg19 Hg38; do for t in BRCAsplicing BRCAfunctionalAssays; do # cp /hive/data/inside/enigmaTracksData/v1.2/$t$db.bb /hive/data/inside/enigmaTracksData/$t$db.bb.tmp # mv /hive/data/inside/enigmaTracksData/$t$db.bb.tmp /hive/data/inside/enigmaTracksData/$t$db.bb # done; done + +############################################################################# +# BRCAmla: add Zanti et al. 2025 case-control LRs (2026-08-18) RM #37886 + +# At the request of the ENIGMA collaborators, the case-control component of the +# PP4/BP5 multifactorial likelihood track was updated from the iCOGS-derived +# values in Parsons et al. 2019 (20 variants) to the case-control likelihood +# ratios (ccLR) from Zanti et al. 2025 (Nat Commun, PMID 40413188, +# doi 10.1038/s41467-025-59979-6), a case-control analysis of the BRIDGES, +# CARRIERS and UK Biobank cohorts. The old iCOGS values were dropped rather +# than kept alongside because iCOGS overlaps the Zanti cohorts (all 20 variants +# recur in the Zanti data) and keeping both would count the same evidence twice. + +mkdir /hive/data/inside/enigmaTracksData/zantiDraft +# Supplementary Data 4 of the paper saved there as ZantiSuppData4.xlsx +# (also copied to /hive/data/outside/enigma/rawData/ at release). + +# The build script reads the current BRCAmfa bigBeds for both assemblies to +# reuse the existing family-history, co-occurrence, segregation and pathology +# LRs and their coordinates, drops the old case-control column, and merges in +# the Zanti ccLR keyed on transcript:HGVSc. The new combined LR is the product +# of the available evidence types. Variant universe is the union of the current +# track and the Zanti variants with a computable ccLR (Zanti rows with +# suggested code N/A or no ccLR are skipped). The new .as adds per-cohort +# columns (BRIDGES, CARRIERS, UK Biobank) and Zanti's standalone suggested +# code; output is bed9+17. +python3 ~/kent/src/hg/makeDb/scripts/enigma/BRCAmlaZanti.py +# Result: 13,481 variants per assembly (up from 4,436), written as +# BRCAmfaZantiHg38.bb / BRCAmfaZantiHg19.bb in the zantiDraft dir. The script +# also writes directionConflicts.tsv listing the 180 variants where the prior +# multifactorial evidence and the ccLR point in opposite directions; these are +# multiplied through as usual per collaborator consensus (Andreas Laner et al., +# see RM #37886) and a caveat was added to the hub description page. + +# Release, same procedure as the v1.2 update above: copy the verified .bb onto +# the staging filenames the /gbdb symlink chain serves (symlinks untouched), +# then the updated enigma.html and trackDb.txt (dataVersion line added, type +# corrected from bed9+67 to bed9+17) into /hive/data/outside/enigma/. +# for db in Hg19 Hg38; do +# cp /hive/data/inside/enigmaTracksData/zantiDraft/BRCAmfaZanti$db.bb /hive/data/inside/enigmaTracksData/BRCAmfa$db.bb.new +# mv /hive/data/inside/enigmaTracksData/BRCAmfa$db.bb.new /hive/data/inside/enigmaTracksData/BRCAmfa$db.bb +# done