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NM_004656.4:c.67+5G>C
p.? · BAP1
ACMG/AMP
0%
complete
Final classification
VUS
PM2
BAP1
c.67+5G>C
p.?
unknown · exon 2i
Gene context NCBI Gene ↗ OncoKB ↗

BAP1 encodes a nuclear deubiquitinating enzyme that removes ubiquitin from proteins and helps regulate cell proliferation, DNA repair, chromatin remodeling, gene expression, and cell cycle progression. It acts as a tumor suppressor, in part through its interaction with BRCA1. Germline mutations in BAP1 cause a hereditary tumor predisposition syndrome associated with increased risk of malignant mesothelioma, uveal melanoma, cutaneous melanoma, and renal cell carcinoma. Somatic BAP1 mutations are also common in these tumor types, highlighting its key role in cancer.

This variant

This intronic BAP1 variant occurs in a tumor-suppressor gene whose germline disruption causes hereditary tumor predisposition involving mesothelioma, melanomas, and renal cell carcinoma.

Transcript
NM_004656.4
HGVS · transcript:coding
NM_004656.4:c.67+5G>C
GRCh38
chr3:52409709 C>G
GRCh37
chr3:52443725 C>G
VUS: PM2 (supporting) is the only met criterion and does not satisfy any generic ACMG/AMP pathogenic or benign combination rule.
Classification rationale
PM2 VUS
BAP1 c.67+5G>C unknown · exon 2i

VUS: PM2 supporting is met because gnomAD allele frequencies are below the <=0.0001 threshold.

PM2 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_004656.4 · variants mapped to exon structure
BAP1 NM_004656.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at supporting strength: gnomAD v2.1 all-comers AF 1.99103e-05 is below the <=0.0001 PM2 Supporting threshold.
gnomAD v2.1 exomes reports 5/251126 alleles, AF 1.99103e-05, and zero homozygotes; gnomAD v4.1 reports 24/1614030 alleles, AF 1.48696e-05, and zero homozygotes.The highest ancestry-specific frequencies are 4.40498e-05 in gnomAD v2.1 European non-Finnish and 2.03384e-05 in gnomAD v4.1 European non-Finnish, both below 0.0001.The supplied ClinGen SVI recommendation downgrades PM2 to Supporting at allele frequency <=0.0001 (PMID:25741868).
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
Assessed · not applied · 7 not met · 11 not assessed
Pathogenic
PVS1 Not met: the intronic +5 variant has no established null consequence, and SpliceAI max delta is 0.161, below the 0.2 splice-impact threshold.
PS2 Not assessed: no proband-parent genotypes or confirmed parental testing are documented for this variant.
PS3 Not assessed: no variant-specific RNA or protein assay was reported, and SpliceAI max delta 0.161 is computational rather than functional evidence.
PS4 Not assessed: no exact-variant case-control dataset, affected-carrier count, control-carrier count, or enrichment statistic is available.
PM6 Not assessed: no apparently de novo occurrence without parental testing is documented in an affected proband.
PP1 Not assessed: zero informative affected-relative transmissions or meioses are documented for this variant.
PP3 Not met: SpliceAI maximum delta 0.161 is below the >=0.2 supporting PP3 threshold.
PP4 Not assessed: no exact-variant carrier phenotype is documented, so phenotype specificity for BAP1-related disease cannot be evaluated.
PP5 Not met: the exact ClinVar record has 0 expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification.
Benign
BA1 Not met: the highest all-comers gnomAD allele frequency is 1.99103e-05, far below the 0.05 BA1 stand-alone threshold.
BS1 Not met: the highest all-comers gnomAD allele frequency is 1.99103e-05, below the 0.01 generic BS1 threshold.
BS2 Not assessed: gnomAD reports zero homozygotes but provides no phenotype-confirmed healthy-carrier or penetrance evidence required for BS2.
BS3 Not assessed: no validated benign RNA or protein assay was reported, and SpliceAI max delta 0.161 cannot demonstrate normal BAP1 function.
BS4 Not assessed: no informative non-segregation observation, such as an affected relative lacking the variant, is documented.
BP2 Not assessed: no confirmed cis phase or affected-proband co-occurrence with a pathogenic BAP1 variant is reported for c.67+5G>C.
BP4 Not met: SpliceAI maximum delta 0.161 exceeds the <=0.1 supporting BP4 threshold.
BP5 Not assessed: no affected exact-variant carrier with an alternative molecular diagnosis is documented for BP5 evaluation.
BP6 Not met: the exact ClinVar record has 0 expert-panel submissions, so laboratory Likely benign assertions cannot trigger BP6.
N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.48696e-05; MAF= 0.00149%, 24/1614030 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.03384e-05; MAF= 0.00203%, 24/1180032 alleles, homozygotes = 0); grpmax FAF= 1.376e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.99103e-05; MAF= 0.00199%, 5/251126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.40498e-05; MAF= 0.00440%, 5/113508 alleles, homozygotes = 0); grpmax FAF= 1.688e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0015% · 24 / 1,614,030
0 hom · FAF 0.0014%
European (non-Finnish)
24 / 1,180,032
0.002%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.002% · 5 / 251,126
0 hom · FAF 0.0017%
European (non-Finnish)
5 / 113,508
0.0044%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 489641)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 4 PMIDs not cited in assessment
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
27748099 ↗ BAP1 Tumor Predisposition Syndrome. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR