3-52406900-C-T

Variant names:

• chr3-52406900-C-T
• rs1193212091
• NM_004656.4:c.588G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004656.4(BAP1):​c.588G>A​(p.Trp196*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BAP1 NM_004656.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• BAP1-related tumor predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Kury-Isidor syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52406900-C-T is Pathogenic according to our data. Variant chr3-52406900-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1750309.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.588G>A	p.Trp196*	stop_gained	Exon 8 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.588G>A	p.Trp196*	stop_gained	Exon 8 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.588G>A	p.Trp196*	stop_gained	Exon 8 of 17	5		ENSP00000296288.5
BAP1	ENST00000471532.5	n.303G>A		non_coding_transcript_exon_variant	Exon 4 of 5	5
BAP1	ENST00000483984.5	n.445G>A		non_coding_transcript_exon_variant	Exon 7 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419272 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 701848

African (AFR) AF: 0.00 AC: 0 AN: 32500

American (AMR) AF: 0.00 AC: 0 AN: 38606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.00 AC: 0 AN: 80936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089446

Other (OTH) AF: 0.00 AC: 0 AN: 58782

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 31, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W196* pathogenic mutation (also known as c.588G>A), located in coding exon 8 of the BAP1 gene, results from a G to A substitution at nucleotide position 588. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This alteration has been detected in an individual with cutaneous melanoma with a family history of uveal melanoma (Popova T et al. Am. J. Hum. Genet., 2013 Jun;92:974-80). This alteration was also detected in an individual with leptomeningeal melanoma and family history of uveal melanoma (de la Fouchardière A et al. Acta Neuropathol., 2015 Jun;129:921-3). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.9
Vest4		0.93
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1193212091; hg19: chr3-52440916; COSMIC: COSV56231737; COSMIC: COSV56231737;