7fb0ec3d9354f0bb4b059b0106ecaf5c40889a05 lrnassar Thu Aug 13 15:13:03 2026 -0700 Tier TP53 FLOSSIES BS2 by carrier count; ClinGen wording, per VCEP meeting. refs #37399 Replace the flat BS2 (-4) with the VCEP's carrier-count tiers: 2-3 carriers BS2_Supporting (-1), 4-7 BS2_Moderate (-2), 8+ BS2 (-4); a single carrier does not meet BS2. Carriers = allele_count - hom_count. tp53Flossies.py assigns the tier and color per observation; tp53ProvisionalClass.py reads the tier from the FLOSSIES bed (load_flossies_lookup returns label+points, bs2_evidence picks the strongest matching tier) and feeds the matching point value into the Provisional point sum. Also change the Provisional disclaimer from 'NOT a VCEP classification' to 'NOT a ClinGen classification' in the mouseover, docstring, and AUTOSQL, and drop a now-unused POINTS['BS2'] entry. diff --git src/hg/makeDb/scripts/tp53/tp53Flossies.py src/hg/makeDb/scripts/tp53/tp53Flossies.py index 580695ca24b..d3bcc7b1363 100644 --- src/hg/makeDb/scripts/tp53/tp53Flossies.py +++ src/hg/makeDb/scripts/tp53/tp53Flossies.py @@ -15,99 +15,119 @@ bigBed 9+8 with filterValues on bs2Applies and consequence. """ import argparse import json import os import sys sys.path.insert(0, os.path.dirname(os.path.abspath(__file__))) import tp53FuncLib as lib DEFAULT_OUTDIR = "/hive/users/lrnassar/claude/RM37399/flossies" DEFAULT_SRC = "/hive/users/lrnassar/claude/RM37399/flossies_tp53.json" COLORS = { - 'BS2': '35,159,134', # teal (matches BS1 family in AF track) - 'Informational': '180,180,180', # gray (non-coding observations) + 'BS2': '23,124,106', # dark teal - BS2 (8+ carriers) + 'BS2_Moderate': '46,157,138', # medium teal - BS2_Moderate (4-7) + 'BS2_Supporting': '138,201,189', # light teal - BS2_Supporting (2-3) + 'Observed': '201,201,201', # light gray - coding, <2 carriers (below BS2) + 'Informational': '180,180,180', # gray - non-coding observations } -# Per CSpec GN009 v2.4.0 §BS2: variant observed in cohort of healthy -# adult women >70 weakens disease-causation evidence. We apply BS2 to -# coding-region observations (missense, synonymous, splice). Non-coding -# (UTR / deep intronic) observations are kept in the track for reference -# but flagged "Informational" since BS2 is not standardly applied to -# non-coding TP53 changes. +# Per CSpec GN009 v2.4.0 §BS2: variant observed in a cohort of healthy +# adult women >70 weakens disease-causation evidence. The VCEP weights BS2 +# by the number of carriers in the cohort: 2-3 -> BS2_Supporting, 4-7 -> +# BS2_Moderate, 8+ -> BS2. In the FLOSSIES TP53 export the coding +# observations that carry a consequence in CODING_CONSEQUENCES are all +# missense; those with a single carrier are shown but do not meet BS2. All +# other observations (synonymous, labeled "silent" here, plus UTR / deep +# intronic) are flagged "Informational" since BS2 is not applied to them. CODING_CONSEQUENCES = { 'missense_variant', 'synonymous_variant', 'splice_donor_variant', 'splice_acceptor_variant', 'splice_region_variant', 'stop_gained', 'stop_lost', 'start_lost', 'frameshift_variant', 'inframe_insertion', 'inframe_deletion', } AUTOSQL = """table TP53Flossies "TP53 VCEP BS2 evidence: observations in the FLOSSIES healthy-women-over-70 cohort" ( string chrom; "Reference sequence chromosome or scaffold" uint chromStart; "Start position in chromosome" uint chromEnd; "End position in chromosome" string name; "Variant display name" uint score; "Not used, all 0" char[1] strand; "Not used, all ." uint thickStart; "Same as chromStart" uint thickEnd; "Same as chromEnd" uint reserved; "RGB color" - string bs2Applies; "BS2 / Informational" - string points; "Tavtigian points (-4 for BS2, 0 for Informational)" + string bs2Applies; "BS2 / BS2_Moderate / BS2_Supporting / Observed / Informational" + string points; "Tavtigian points (BS2 -4, Moderate -2, Supporting -1, else 0)" string consequence; "Predicted consequence (missense, synonymous, UTR, etc.)" string hgvsc; "HGVSc cDNA notation" string hgvsp; "HGVSp protein notation (if coding)" uint alleleCount; "Allele count across the FLOSSIES cohort" uint alleleNum; "Total allele count (cohort size x 2)" string popBreakdown; "Per-population AC/AN" string genomicRef; "Genomic reference allele (matches chromStart base on + strand)" string genomicAlt; "Genomic alternate allele" lstring _mouseOver; "HTML mouseover" ) """ -def categorize(consequence): - """Return ('BS2', '-4 pts') or ('Informational', '0 pts').""" - if consequence in CODING_CONSEQUENCES: - return ('BS2', '-4 pts') - return ('Informational', '0 pts') +def bs2_tier(consequence, carriers): + """Return (label, points_str, points_int) per CSpec GN009 v2.4.0 BS2 count + tiers: 2-3 carriers -> BS2_Supporting, 4-7 -> BS2_Moderate, 8+ -> BS2. + Coding observations with a single carrier are shown but do not meet BS2; + non-coding observations are Informational only.""" + if consequence not in CODING_CONSEQUENCES: + return ('Informational', '0 pts', 0) + if carriers >= 8: + return ('BS2', '-4 pts', -4) + if carriers >= 4: + return ('BS2_Moderate', '-2 pts', -2) + if carriers >= 2: + return ('BS2_Supporting', '-1 pt', -1) + return ('Observed', '0 pts', 0) -def mouseover(disp, hgvsc, hgvsp, conseq, applies, pts, +def mouseover(disp, hgvsc, hgvsp, conseq, applies, pts, carriers, ac, an, pop_acs, pop_ans): pop_lines = [] for pop in pop_acs: an_p = pop_ans.get(pop, 0) or 0 ac_p = pop_acs.get(pop, 0) or 0 if an_p: pop_lines.append("{}: {}/{} ({:.4f})".format( pop, ac_p, an_p, ac_p / an_p)) else: pop_lines.append("{}: {}/{}".format(pop, ac_p, an_p)) af = (ac / an) if an else 0.0 bs2_section = "" - if applies == 'BS2': + if applies in ('BS2', 'BS2_Moderate', 'BS2_Supporting'): bs2_section = ( - "<br><b>BS2 applicability:</b> Yes ({} pts) " - "— coding observation in healthy aged-female cohort" - ).format(pts) + "<br><b>BS2 applicability:</b> {applies} ({pts}) " + "— {carriers} carrier(s) in cohort " + "(GN009 tiers: 2–3 Supporting, 4–7 Moderate, 8+ Strong)" + ).format(applies=applies, pts=pts, carriers=carriers) + elif applies == 'Observed': + bs2_section = ( + "<br><b>BS2 applicability:</b> Not met — only {carriers} " + "carrier(s); GN009 requires ≥2 carriers for BS2_Supporting" + ).format(carriers=carriers) else: bs2_section = ( "<br><b>BS2 applicability:</b> Informational only " "— non-coding consequence; BS2 is not standardly applied " "to TP53 UTR/intronic changes per CSpec GN009" ) hgvsp_line = "" if hgvsp: hgvsp_line = "<br><b>Protein:</b> {}".format(hgvsp) return ( "<b>FLOSSIES observation (BS2 evidence)</b>" "<br><b>Variant:</b> {disp}" "<br><b>cDNA:</b> {hgvsc}" "{hgvsp_line}" "<br><b>Consequence:</b> {cons}" @@ -163,45 +183,47 @@ skipped = 0 for v in records: ref = v['ref'] alt = v['alt'] pos_hg19 = int(v['pos']) if assembly == 'hg19': chrom = "chr{}".format(v['chrom']) start = pos_hg19 - 1 end = start + len(ref) else: if v['variant_id'] not in hg38_lookup: skipped += 1 continue chrom, start, end = hg38_lookup[v['variant_id']] conseq = v.get('major_consequence') or 'unknown' - applies, pts = categorize(conseq) + ac = int(v.get('allele_count') or 0) + an = int(v.get('allele_num') or 0) + hom = int(v.get('hom_count') or 0) + carriers = ac - hom # individuals: het + hom = allele_count - hom_count + applies, pts, _ = bs2_tier(conseq, carriers) color = COLORS[applies] hgvsc = v.get('HGVSc') or '' hgvsp = v.get('HGVSp') or '' - ac = int(v.get('allele_count') or 0) - an = int(v.get('allele_num') or 0) pop_acs = v.get('pop_acs') or {} pop_ans = v.get('pop_ans') or {} pop_breakdown = "; ".join( "{}={}/{}".format(p, pop_acs.get(p, 0), pop_ans.get(p, 0)) for p in pop_acs ) disp = "{}:{}{}>{}".format(chrom, start + 1, ref, alt) name = hgvsp if hgvsp else (hgvsc if hgvsc else disp) - mo = mouseover(disp, hgvsc, hgvsp, conseq, applies, pts, + mo = mouseover(disp, hgvsc, hgvsp, conseq, applies, pts, carriers, ac, an, pop_acs, pop_ans) lines.append("\t".join([ chrom, str(start), str(end), name, "0", ".", str(start), str(end), color, applies, pts, conseq, hgvsc, hgvsp, str(ac), str(an), pop_breakdown, ref, alt, mo, ])) if skipped: print(" liftOver dropped {} variants".format(skipped)) return lines @@ -212,32 +234,32 @@ records = load_flossies(src_json) print(" {} FLOSSIES records loaded".format(len(records))) from collections import Counter consequences = Counter(r.get('major_consequence') for r in records) print(" Consequences: {}".format(dict(consequences))) if db == 'hg38': hg38_lookup = hg19_to_hg38_lift(records, outdir) print(" liftOver matched {}/{} variants".format( len(hg38_lookup), len(records))) lines = emit_rows(records, 'hg38', hg38_lookup) else: lines = emit_rows(records, 'hg19', None) print(" {} BED rows".format(len(lines))) - bs2_count = sum(1 for L in lines if "\tBS2\t" in L) - print(" BS2 applicable: {}".format(bs2_count)) + tiers = Counter(L.split("\t")[9] for L in lines) + print(" BS2 tiers: {}".format(dict(tiers))) as_file = os.path.join(outdir, "TP53Flossies.as") lib.write_autosql(as_file, AUTOSQL) bed = os.path.join(outdir, "TP53Flossies_{}.bed".format(db)) with open(bed, 'w') as f: f.write("\n".join(lines) + "\n") lib.run_sort_bed(bed) bb = os.path.join(outdir, "TP53Flossies{}.bb".format(db.capitalize())) lib.run_bedToBigBed(bed, as_file, bb, lib.chrom_sizes_path(db), "bed9+10") print(" wrote {}".format(bb)) def main(): p = argparse.ArgumentParser(description=__doc__) p.add_argument('-o', '--output-dir', default=DEFAULT_OUTDIR)