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

This variant is an intronic substitution (c.37+28G>A) in intron 1 of BAP1. SpliceAI predicts no splice impact (max delta = 0.00).

2

Two reputable clinical laboratories have independently classified this variant as Likely benign in ClinVar (Variation ID: 2906656).

3

The variant is present in gnomAD at low frequency: 0.0107% in v2.1 (30/279376 alleles) and 0.0193% in v4.1 (312/1612888 alleles), with no homozygotes in any database. This frequency is below the PM2 threshold of 0.1%.

4

Applying generic ACMG/AMP 2015 combination rules: one supporting pathogenic criterion (PM2) is outweighed by two supporting benign criteria (BP4, BP6), supporting a Likely benign classification.

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 variant is an intronic substitution (c.37+28G>A) located in intron 1 at position +28 from the exon 1 donor site. It does not fall into any ClinGen PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI predicts no splice impact (max delta = 0.00). PVS1 is not applicable.	spliceai pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires a different pathogenic missense variant at the same amino acid position as the assessed variant. This variant is intronic (c.37+28G>A) and does not alter an amino acid. No protein consequence is predicted.
PS2	Not assessed	PS2 requires a de novo variant with confirmed paternity and maternity. No de novo data are available for this variant in the literature or ClinVar submissions.
PS3	Not assessed	PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect. No functional studies specific to NM_004656.4:c.37+28G>A were identified in the literature. The ClinVar-cited PMID 25741868 (ACMG guidelines) is a methodology paper that does not mention this variant.
PS4	Not assessed	PS4 requires the variant prevalence in affected individuals to be significantly increased compared to controls. While the variant is present in gnomAD at low frequency (v2.1: 30/279376, v4.1: 312/1612888), no case-control study or formal statistical comparison has been performed for this variant.	gnomad_v2 gnomad_v4
PS5	Not assessed	PS5 requires a de novo variant with confirmed paternity and maternity, where the variant is also reported as pathogenic by a reputable source. No de novo data are available for this variant.
PM1	Not met	PM1 requires the variant to be located in a mutational hotspot or well-established critical functional domain. This variant is in intron 1 at position +28, not within any known functional domain, mutational hotspot, or critical residue. Hotspot analysis confirms the residue is not significant and the exact variant is not listed in any hotspot database.
PM2	Met	This variant is present in gnomAD at very low frequency: 0.0107% in v2.1 (30/279376 alleles) and 0.0193% in v4.1 (312/1612888 alleles), both well below the 0.1% threshold for PM2 in non-VCEP contexts. The variant is absent from gnomAD-Canada. No homozygotes are observed in any database.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This variant is intronic (c.37+28G>A) and does not alter an amino acid. Protein consequence is indeterminate (NP_004647.1:p.?). PM5 candidate harvesting confirmed no eligible comparator variants.	pm5_candidates
PM6	Not assessed	PM6 requires a de novo variant with confirmed paternity and maternity. No de novo data are available for this variant.
PP1	Not assessed	PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. This variant is an intronic substitution (c.37+28G>A), not a missense variant.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this intronic variant. HCI prior is not supported for BAP1. No in silico evidence supports a damaging effect.	spliceai
PP4	Not assessed	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No proband phenotype information is available for this case.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. ClinVar reports this variant as Likely benign from two clinical laboratories (SCV007129130, SCV004535795). No credible source reports this variant as pathogenic.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. This variant has an allele frequency of 0.0107% in gnomAD v2.1 and 0.0193% in gnomAD v4.1, both far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases (non-VCEP threshold). This variant has an allele frequency of 0.0107% in gnomAD v2.1 (grpmax FAF 0.016%) and 0.0193% in gnomAD v4.1 (grpmax FAF 0.022%), both well below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. BAP1 tumor predisposition syndrome has incomplete penetrance (estimated 60-70%) and adult onset (median cancer diagnosis in the 40s-50s). The presence of this variant in gnomAD (30-312 heterozygotes) does not satisfy BS2 because reduced penetrance and late onset mean healthy adults in population databases may not have expressed the phenotype yet.	gnomad_v2 gnomad_v4
BS3	Not assessed	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies specific to NM_004656.4:c.37+28G>A were identified. While SpliceAI predicts no splice impact (max delta = 0.00), this is in silico evidence covered under BP4, not BS3-level functional data.
BS4	Not assessed	BS4 requires lack of segregation in affected members of a family. No segregation data are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. BAP1 is indeed a gene where loss-of-function/truncating variants are the primary disease mechanism, but the assessed variant is intronic (c.37+28G>A), not a missense variant. BP1 is not applicable.
BP2	Not assessed	BP2 requires observation of the variant in trans with a pathogenic variant in a dominant disorder, or in cis with a pathogenic variant. No phasing data are available for this variant.
BP4	Met	SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00). No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. For an intronic variant where splicing is the primary functional concern, the absence of any predicted splice alteration supports a benign interpretation.	spliceai
BP5	Not assessed	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant.
BP6	Met	Two reputable clinical testing laboratories have classified this variant as Likely benign in ClinVar: Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital (SCV007129130) and Labcorp Genetics, formerly Invitae (SCV004535795). Both submissions provide criteria for their classification (review status: criteria provided, single submitter). This meets BP6 criteria for a reputable source reporting the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. This variant is an intronic substitution (c.37+28G>A), not a synonymous exonic variant. BP7 is not applicable to intronic variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.