Variant classification summary

NM_004656.4:c.121G>A

BAP1 · NP_004647.1:p.(Gly41Ser) · NM_004656.4

GRCh37: chr3:52443571 C>T · GRCh38: chr3:52409555 C>T

Gene: BAP1 Transcript: NM_004656.4

Final call

Likely Benign

BS4 supporting BP4 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Gly41Ser)

gnomAD AF

0.0003679932596520791 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS4 supporting from discordant cosegregation in the reported family.

2

Likely Benign: BP4 supporting from REVEL 0.072 and SpliceAI max delta 0.009 below benign-evidence thresholds.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting benign criteria (BS4 and BP4) lead to a Likely Benign classification.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004656.4:c.121G>A in BAP1 is a missense substitution predicted to produce NP_004647.1:p.(Gly41Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the exact p.Gly41Ser change is reported as benign or probably benign, with no established pathogenic same-amino-acid comparator.	clinvar PMID:22683710 PMID:23709298 PMID:26166446
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo status is documented for NM_004656.4:c.121G>A.	PMID:22683710 PMID:23709298
PS3	Not assessed	Not assessed: no validated functional assay with controls or quantitative activity result was reported for BAP1 p.Gly41Ser.	PMID:22683710 PMID:23709298 PMID:26166446 PMID:24728327 PMID:26554828
PS4	Not met	Not met: the exact variant was reported in one RCC-family individual, but cosegregation did not support causality and no case-control enrichment statistic is available.	PMID:22683710 PMID:23709298 PMID:26166446
PM1	Not assessed	Not assessed: the available review places BAP1 catalytic activity near the N-terminus but gives no precise validated boundary confirming residue 41 as a critical domain site.	PMID:26166446
PM2	Not met	Not met: gnomAD v4.1 all-comers AF 0.0003679932596520791 exceeds the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: BAP1 tumor predisposition is autosomal dominant, with no affected-proband biallelic or in-trans configuration reported for c.121G>A.	PMID:23709298 PMID:22683710
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004656.4:c.121G>A in BAP1 is a missense substitution predicted to produce NP_004647.1:p.(Gly41Ser). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no established pathogenic alternate missense change at residue 41 was identified, and the cited Leu14His comparator is at residue 14.	pm5_candidates PMID:22683710 PMID:23709298 PMID:26166446
PM6	Not assessed	Not assessed: the exact variant is reported without parental testing or a stated presumed de novo event.	PMID:22683710 PMID:23709298
PP1	Not met	Not met: cosegregation studies suggested c.121G>A (p.Gly41Ser) was not responsible for the family's cancer predisposition.	PMID:23709298
PP2	Not assessed	Not assessed: BAP1 missense biology is documented, but no validated gene-level benign-missense depletion metric or threshold is available for PP2.	PMID:26166446
PP3	Not met	Not met: REVEL 0.072 and SpliceAI max delta 0.009 are below PP3 supporting thresholds of 0.644 and 0.2, respectively.	revel spliceai bayesdel
PP4	Not assessed	Not assessed: a renal cell carcinoma family history is reported, but the patient's phenotype is not sufficiently documented to establish disease specificity.	PMID:23709298
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification; available submissions are laboratory Benign or Likely benign.	clinvar
BA1	Not met	Not met: the highest observed population frequency was 0.004442121766396656, below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed population frequency was 0.004442121766396656, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports six homozygotes, but their health status, age, and BAP1-specific phenotype are unavailable for the generic BS2 requirement.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated functional assay with controls demonstrated normal BAP1 function for p.Gly41Ser.	PMID:22683710 PMID:23709298 PMID:26166446 PMID:24728327 PMID:26554828
BS4	Met	Met, supporting: cosegregation studies suggested c.121G>A (p.G41S) did not track with the family's cancer predisposition.	PMID:23709298
BP1	Not met	Not met: truncating variants account for 36% of reported BAP1 tumor mutations, while functional effects are documented for multiple missense variants.	PMID:26166446
BP2	Not assessed	Not assessed: the reported c.121G>A family study provides no identified pathogenic partner variant or confirmed cis/trans phase required for BP2.	PMID:23709298 PMID:26166446
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004656.4:c.121G>A in BAP1 is a missense substitution predicted to produce NP_004647.1:p.(Gly41Ser). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: REVEL 0.072 is <=0.29 and SpliceAI max delta 0.009 is <=0.1, meeting calibrated BP4 thresholds.	revel spliceai bayesdel
BP5	Not assessed	Not assessed: the report notes negative germline VHL testing, but provides no alternative pathogenic molecular cause explaining an affected patient's phenotype.	PMID:23709298 PMID:22683710
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification; available benign labels are ordinary laboratory submissions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004656.4:c.121G>A in BAP1 is a missense substitution predicted to produce NP_004647.1:p.(Gly41Ser). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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