rs776606194

chr3-52404490-CGTCATCCTCATA-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004656.4(BAP1):c.1201_1212del(p.Tyr401_Asp404del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000235 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y401Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: BAP1 NM_004656.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 6.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAP1	NM_004656.4	c.1201_1212del	p.Tyr401_Asp404del	inframe_deletion	12/17	ENST00000460680.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAP1	ENST00000460680.6	c.1201_1212del	p.Tyr401_Asp404del	inframe_deletion	12/17	1	NM_004656.4	P1
BAP1	ENST00000296288.9	c.1147_1158del	p.Tyr383_Asp386del	inframe_deletion	12/17	5
BAP1	ENST00000490804.1	n.629_640del		non_coding_transcript_exon_variant	2/3	2
BAP1	ENST00000469613.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000643 AC: 16 AN: 248820 Hom.: 0 AF XY: 0.0000668 AC XY: 9 AN XY: 134766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

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: 0.00000899

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461872 Hom.: 0 AF XY: 0.0000193 AC XY: 14 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 23, 2023	This variant is causes a 4 amino acid deletion of codons 401 to 404 in exon 12 of the BAP1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with kidney cancer (PMID: 29684080) and an individual affected with gastrointestinal neuroendocrine neoplasms (PMID: 36653904). This variant has been identified in 17/280226 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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2023	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

BAP1-related tumor predisposition syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This variant, c.1201_1212del, results in the deletion of 4 amino acid(s) of the BAP1 protein (p.Tyr401_Asp404del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776606194, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412428). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 23, 2023	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	In-frame deletion of 4 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Observed in an individual with kidney cancer in published literature (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 36653904) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 13, 2019	- -

BAP1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The BAP1 c.1201_1212del12 variant is predicted to result in an in-frame deletion (p.Tyr401_Asp404del). This variant has been reported in a kidney renal clear cell carcinoma from The Cancer Genome Atlas (TCGA), as well as a gastrointestinal neuroendocrine neoplasm (Table S9, TCGA ID KIRC_3351-11A Yehia et al. 2018. PubMed ID: 29684080; Table 3, Dai et al. 2023. PubMed ID: 36653904). This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/412428/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs776606194; hg19: chr3-52438506;