chr3-52404529-G-A

Variant names:

• chr3-52404529-G-A
• rs1553645146
• NM_004656.4:c.1174C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.1174C>T​(p.Gln392*) 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)
• Consequence: BAP1 NM_004656.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.71

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 Pathogenic. Variant got 18 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 3-52404529-G-A is Pathogenic according to our data. Variant chr3-52404529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 490777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1174C>T	p.Gln392*	stop_gained	Exon 12 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1174C>T	p.Gln392*	stop_gained	Exon 12 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.1120C>T	p.Gln374*	stop_gained	Exon 12 of 17	5		ENSP00000296288.5
BAP1	ENST00000490804.1	n.602C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
BAP1	ENST00000469613.5	c.-54C>T		upstream_gene_variant		1		ENSP00000418320.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:2

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln392*) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with BAP1-related cancer (PMID: 30517737). ClinVar contains an entry for this variant (Variation ID: 490777). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q392* pathogenic mutation (also known as c.1174C>T), located in coding exon 12 of the BAP1 gene, results from a C to T substitution at nucleotide position 1174. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration was identified in multiple individuals with a personal and/or family history of BAP1-related disease (Walpole S et al. J Natl Cancer Inst, 2018 12;110:1328-1341). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Feb 05, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 12 of the BAP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with rhabdoid meningioma (PMID: 29981911). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Melanoma, uveal, susceptibility to, 2;C3280492:BAP1-related tumor predisposition syndrome;C5676925:Kury-Isidor syndrome Pathogenic:1

Jun 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.95
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553645146; hg19: chr3-52438545; COSMIC: COSV56238008; COSMIC: COSV56238008;