rs373910684

Positions:

• chr3-52409839-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004656.4(BAP1):​c.37+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BAP1 NM_004656.4 splice_region, intron
• Scores: Splicing: ADA: 0.01023
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.01

Genes affected

BAP1 (HGNC:950): (BRCA1 associated protein 1) This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

BAP1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4	c.37+3G>A		splice_region_variant, intron_variant		ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.37+3G>A		splice_region_variant, intron_variant		1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.37+3G>A		splice_region_variant, intron_variant		5		ENSP00000296288.5
BAP1	ENST00000483984.5	n.37+3G>A		splice_region_variant, intron_variant		3
BAP1	ENST00000490917.1	n.37+3G>A		splice_region_variant, intron_variant		5		ENSP00000419709.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247140 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134456

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2021	This variant causes a G to A nucleotide substitution at the +3 position of intron 1 of the BAP1 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/247140 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 15, 2023	The c.37+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 1 in the BAP1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

BAP1-related tumor predisposition syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis provides insufficient evidence to determine the effect of this variant on BAP1 splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 472698). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 1 of the BAP1 gene. It does not directly change the encoded amino acid sequence of the BAP1 protein. It affects a nucleotide within the consensus splice site. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 11, 2024	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373910684; hg19: chr3-52443855; COSMIC: COSV99964400; COSMIC: COSV99964400;