NM_004656.4:c.86T>G

BAP1 · NP_004647.1:p.(Val29Gly) · NM_004656.4

GRCh37: chr3:52443606 A>C · GRCh38: chr3:52409590 A>C

Gene: BAP1 Transcript: NM_004656.4

Final call

VUS

PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Val29Gly)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004656.4:c.86T>G (p.Val29Gly) in BAP1 is a missense variant in exon 3, located within the ubiquitin C-terminal hydrolase (UCH) domain.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.

The variant resides in the UCH domain, a critical functional domain of BAP1 without evidence of benign variation at this residue, meeting PM1 at moderate strength as assigned by the Walpole et al. 2018 global cohort study.

Computational evidence supports a deleterious effect: REVEL score 0.77 exceeds commonly used thresholds, and Walpole et al. explicitly assigned PP3 to p.V29G, meeting PP3 at supporting strength.

A saturation genome editing study of BAP1 (PMID:38969833) was reviewed in full but did not include p.Val29Gly; the Ambry Genetics ClinVar PS3 functional signal citing this paper could not be validated.

No variant-specific functional studies, de novo observations, or segregation data sufficient to meet PS3, PS2, or PP1 were identified.

With two moderate criteria (PM1, PM2) and one supporting criterion (PP3) met, and no benign criteria met, this variant does not reach the likely pathogenic threshold (requires ≥3 moderate, or 2 moderate + 2 supporting) under the generic ACMG/AMP 2015 classification framework and is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Missense variant (c.86T>G, p.Val29Gly) does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework is not applicable to this class of variant.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	PS1 requires a different nucleotide change at the same codon producing the same missense change (p.Val29Gly) with established pathogenicity. No such comparator variant was identified in the evidence packet, ClinVar records, or publications.
PS2	Not assessed	PS2 requires de novo confirmation with both maternity and paternity confirmed. No de novo testing data for this variant was available in the evidence packet, ClinVar submissions, or reviewed literature.
PS3	Not met	Well-established functional studies supporting a damaging effect were not identified. The Ambry Genetics ClinVar submission (SCV006197225) cited PMID:38969833 for functional evidence, but full-text review confirmed that NM_004656.4:c.86T>G (p.Val29Gly) is not mentioned in that saturation genome editing study. No other variant-specific functional assays were found.	clinvar PMID:38969833
PS4	Not met	PS4 requires a statistically enriched observation of the variant in affected individuals versus controls. PMID:30517737 includes p.V29G in a global BAP1-TPDS cohort but does not provide sufficient case counts or control comparison data to support PS4. The variant was listed among six missense variants with 'some evidence of pathogenicity' but insufficient to reach likely pathogenic threshold.	PMID:30517737 clinvar
PS5	Not met	No reputable source has definitively classified this variant as pathogenic with evidence available for independent evaluation. ClinVar shows conflicting classifications: two submitters report Uncertain significance; one submitter (Ambry Genetics) reports Likely pathogenic, but the cited functional evidence (PMID:38969833) does not mention this variant. This does not meet PS5 threshold.	clinvar
PM1	Met	p.Val29Gly is located in the ubiquitin C-terminal hydrolase (UCH) domain of BAP1, a well-established critical functional domain. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating no benign variation at this residue. PMID:30517737 explicitly assigns PM1 to p.V29G in its ACMG assessment.	PMID:30517737 gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes+genomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PM2 threshold of <0.1% in all population databases examined.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per instruction.
PM4	N/A	Skipped per instruction.
PM5	N/A	Unable to confirm classic same-residue PM5 semantics safely; no candidate comparator variants at codon 29 with an established pathogenic classification were identified. The automated pm5_candidates harvest returned zero candidates.	pm5_candidates
PM6	Not assessed	PM6 requires a de novo observation with maternity and paternity confirmed. No de novo evidence for NM_004656.4:c.86T>G was identified in ClinVar submissions, publications, or the evidence packet.
PP1	Not met	PP1 requires co-segregation with disease in multiple affected family members. PMID:30517737 states that the six variants including p.V29G have 'some have varying levels of PP1 and PP4,' but does not confirm whether p.V29G specifically meets PP1. Without the Supplementary Table 2 data, co-segregation evidence cannot be attributed to this specific variant.	PMID:30517737
PP2	Not met	PP2 applies to genes with a low rate of benign missense variation where missense variants are a common disease mechanism. For BAP1, the primary disease mechanism is loss of function (nonsense, frameshift, splice). Missense variants account for a small proportion of known pathogenic BAP1 variants, and >98% of observed missense variants are classified as VUS. PP2 is not met.
PP3	Met	Multiple lines of computational evidence support a deleterious effect on the gene product. REVEL score is 0.77, exceeding the 0.5 and 0.75 thresholds used by many clinical laboratories. PMID:30517737 explicitly assigns PP3 to p.V29G. SpliceAI predicts no splice impact (max delta 0.03), which is not contradictory — this is a missense, not splice variant.	revel spliceai PMID:30517737
PP4	Not met	PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease. PMID:30517737 mentions 'some have varying levels of PP4' among the six variants including p.V29G, but without specific patient-level phenotype data for this variant, PP4 cannot be independently confirmed.	PMID:30517737
PP5	Not met	No reputable source has definitively classified this variant as pathogenic. ClinVar contains conflicting classifications: two clinical laboratories report Uncertain significance, and one reports Likely pathogenic (Ambry Genetics), but the Ambry classification cited functional evidence (PMID:38969833) that does not contain this variant. No expert panel review is available.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires allele frequency >0.3% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No such evidence is available for this variant.
BS3	Not met	BS3 requires well-established functional studies showing no damaging effect. No functional studies of p.Val29Gly demonstrating a benign effect were identified.
BS4	Not met	BS4 requires lack of segregation in affected family members. No segregation data demonstrating absence of co-segregation were identified.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. Although BAP1-TPDS is predominantly caused by null variants, pathogenic missense variants in BAP1 are well-documented, including three reaching likely pathogenic classification in PMID:30517737, and missense variants in BAP1 cause Kury-Isidor syndrome (PMID:35051358). Therefore BP1 does not apply.	PMID:30517737
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such evidence is available.
BP3	N/A	Skipped per instruction.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.77 supports a deleterious effect, and SpliceAI max delta of 0.03 is not informative for a missense variant. BayesDel 0.315 is below typical damaging thresholds but does not constitute 'multiple lines' of benign computational evidence. BP4 is not met.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such evidence was identified.
BP6	Not met	BP6 requires a reputable source to report the variant as benign. ClinVar classification for this variant is Uncertain significance (2 submitters) and Likely pathogenic (1 submitter). No submitter has classified this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants. NM_004656.4:c.86T>G is a missense variant producing p.Val29Gly.

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