Variant classification summary

NM_004656.4:c.37+28G>A

BAP1 · NP_004647.1:p.? · NM_004656.4

GRCh37: chr3:52443830 C>T · GRCh38: chr3:52409814 C>T

Gene: BAP1 Transcript: NM_004656.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.?

gnomAD AF

0.0001934418260908383 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004656.4:c.37+28G>A is an intronic variant located at position +28 in intron 1 of BAP1.

2

This variant is present in gnomAD population databases at low frequency: 0.011% (30/279,376 alleles) in v2.1 and 0.019% (312/1,612,888 alleles) in v4.1, with no homozygotes observed.

3

SpliceAI predicts no splice-altering effect, with a maximum delta score of 0.00 across all splice site categories.

4

Two independent clinical laboratories have classified this variant as Likely benign in ClinVar (ClinVar variation ID 2906656).

5

No functional studies, case-control data, segregation data, or de novo observations have been identified for this variant in the reviewed literature.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	This is an intronic substitution variant (c.37+28G>A) and does not fall into the default generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	This is an intronic variant; there is no amino acid change to compare against known pathogenic missense changes at the same residue.
PS2	N/A	No de novo observation data are available for this variant.
PS3	Not met	No functional studies have been identified for this variant. None of the associated publications (PMIDs 25741868, 27748099, 28492532) contain variant-specific functional data; they are guideline and review articles.	PMID:25741868 PMID:27748099 PMID:28492532
PS4	Not met	No case-control data demonstrate enrichment of this variant in affected individuals versus controls. The variant is present in gnomAD population databases at low frequency (v2.1: 30/279,376 alleles; v4.1: 312/1,612,888 alleles).	gnomad_v2 gnomad_v4
PS5	N/A	No evidence that this is a founder variant.
PM1	N/A	This is an intronic variant, not located in a mutational hot spot or well-established critical functional domain. No hotspot or domain-level pathogenicity enrichment detected.
PM2	Met	This variant is present at very low frequency in population databases. In gnomAD v2.1 the allele frequency is 0.011% (30/279,376 alleles) and in gnomAD v4.1 it is 0.019% (312/1,612,888 alleles), both below the 0.1% PM2 threshold for dominant disorders. No homozygotes have been observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This is an intronic variant; no amino acid residue can be identified for PM5 comparator analysis. PM5 candidate harvesting confirmed ineligible.	pm5_candidates
PM6	N/A	No de novo observation data are available for this variant.
PP1	Not assessed	No segregation data are available to evaluate cosegregation of this variant with disease in affected families.
PP2	N/A	This is an intronic variant, not a missense change. PP2 applies specifically to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	SpliceAI predicts no splice-altering effect (max delta score = 0.00). REVEL, BayesDel, and HCI prior are not applicable to this intronic variant. No computational evidence supports a pathogenic effect.	spliceai
PP4	N/A	No detailed phenotype information is available to assess whether the proband's clinical presentation is highly specific for BAP1-related tumor predisposition syndrome.
PP5	N/A	The ClinVar classification for this variant is Likely benign from two clinical laboratories, not Pathogenic. PP5 requires a reputable source to have classified the variant as pathogenic. No expert panel has classified this variant.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 0.019% (312/1,612,888 alleles), which is below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 0.019%, which is below the 0.3% BS1 threshold. The variant is not present at a frequency high enough to support a benign interpretation by population data alone.	gnomad_v2 gnomad_v4
BS2	N/A	No homozygous individuals have been observed in gnomAD v2.1 or v4.1. BS2 requires observation in a healthy adult homozygous state for a fully penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect have been identified for this variant. None of the associated publications contain variant-specific functional evidence.	PMID:25741868 PMID:27748099 PMID:28492532
BS4	Not assessed	No segregation data are available to evaluate lack of cosegregation with disease.
BP1	N/A	This is an intronic variant, not a missense change. BP1 applies specifically to missense variants in a gene where a different pathogenic missense change is known to cause disease through the same mechanism.
BP2	N/A	No data are available regarding observation of this variant in trans with a known pathogenic variant in BAP1.
BP4	Met	SpliceAI predicts no splice-altering effect for this intronic variant (max delta score = 0.00 across all splice site categories: donor gain, donor loss, acceptor gain, acceptor loss). This computational evidence supports a benign interpretation.	spliceai
BP5	N/A	No observation of this variant in a case where an alternate molecular basis for disease has been identified.
BP6	Met	Two independent clinical laboratories have classified this variant as Likely benign in ClinVar: Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital (SCV007129130) and Labcorp Genetics/Invitae (SCV004535795). Both submissions are criteria-provided, supporting a benign interpretation from reputable clinical sources.	clinvar
BP7	N/A	This is an intronic substitution variant, not a synonymous (silent) exonic variant. BP7 applies specifically to synonymous variants with no predicted splice impact.

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