Classification rationale

PM2 BP4BP6 Likely Benign

BAP1 c.37+28G>A

This variant is an intronic substitution (c.37+28G>A) in intron 1 of BAP1. SpliceAI predicts no splice impact (max delta = 0.00).¹ Two reputable clinical laboratories have independently classified this variant as Likely benign in ClinVar (Variation ID: 2906656).² 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%.³ 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.⁴

PM2 + BP4 + BP6 → Likely Benign

1 spliceai ↗

2 clinvar ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 generic_acmg_combination_rules

Gene diagram · NM_004656.4 · variants mapped to exon structure

BAP1 NM_004656.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1 AF = 0.0107% (30/279376)grpmax FAF = 0.000162gnomAD v4.1 AF = 0.0193% (312/1612888)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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 max delta = 0.00No predicted donor/acceptor gain or lossNo REVEL/BayesDel scores available (not missense)

spliceai ↗

✓

BP6 supporting Benign

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 Variation ID 2906656: Likely benignSCV007129130: Likely benign — Center for Genomic MedicineRigshospitalet

clinvar ↗

Assessed · not applied

Pathogenic

PS2 PS2 requires a de novo variant with confirmed paternity and maternity.

PS3 PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect.

PS4 PS4 requires the variant prevalence in affected individuals to be significantly increased compared to controls.

PM1 PM1 requires the variant to be located in a mutational hotspot or well-established critical functional domain.

PM6 PM6 requires a de novo variant with confirmed paternity and maternity.

PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members.

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect.

PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.

PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic.

Benign

BA1 BA1 requires an allele frequency >1% in population databases.

BS1 BS1 requires an allele frequency >0.3% in population databases (non-VCEP threshold).

BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.

BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.

BS4 BS4 requires lack of segregation in affected members of a family.

BP2 BP2 requires observation of the variant in trans with a pathogenic variant in a dominant disorder, or in cis with a pathogenic variant.

BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease.

N/A · 6 PVS1 · PS1 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000193442; MAF= 0.01934%, 312/1612888 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000272226; MAF= 0.02722%, 17/62448 alleles, homozygotes = 0); grpmax FAF= 0.00022226.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000107382; MAF= 0.01074%, 30/279376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227644; MAF= 0.02276%, 29/127392 alleles, homozygotes = 0); grpmax FAF= 0.00016212.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00021772262138036142, 4/18372 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.019% · 312 / 1,612,888
0 hom · FAF 0.022%

Remaining individuals 17 / 62,448	0.027%
European (non-Finnish) 290 / 1,179,948	0.025%
Admixed American 2 / 59,994	0.0033%
African/African American 2 / 74,934	0.0027%
European (Finnish) 1 / 63,106	0.0016%

+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.011% · 30 / 279,376
0 hom · FAF 0.016%

European (non-Finnish) 29 / 127,392	0.023%
Remaining individuals 1 / 7,132	0.014%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

0.022% · 4 / 18,372
0 hom · FAF 0.012%

European (non-Finnish)

4 / 11,706

0.034%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 2906656)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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 ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 3 PMIDs not cited in assessment

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. CLINVAR

27748099 ↗ BAP1 Tumor Predisposition Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?