Classification rationale

PM2 BP4BP6 Likely Benign

BAP1 c.37+28G>A

NM_004656.4:c.37+28G>A is an intronic variant located at position +28 in intron 1 of BAP1. 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.¹ SpliceAI predicts no splice-altering effect, with a maximum delta score of 0.00 across all splice site categories.² Two independent clinical laboratories have classified this variant as Likely benign in ClinVar (ClinVar variation ID 2906656).³ No functional studies, case-control data, segregation data, or de novo observations have been identified for this variant in the reviewed literature.⁴

PM2 + BP4 + BP6 → Likely Benign

1 gnomad_v2 ↗gnomad_v4 ↗

2 spliceai ↗

3 clinvar ↗

4 PMID:25741868 ↗PMID:27748099 ↗PMID:28492532 ↗

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

BAP1 NM_004656.4

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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