rs1553645286

Variant names:

• chr3-52405183-G-A
• rs1553645286
• NM_004656.4:c.1043C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52405183-G-A
• chr3-52405183-G-C
• chr3-52405183-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004656.4(BAP1):​c.1043C>T​(p.Pro348Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.71

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 2.6442 (below the threshold of 3.09). Trascript score misZ: 3.2667 (above the threshold of 3.09). GenCC associations: The gene is linked to BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17791641).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1043C>T	p.Pro348Leu	missense_variant	Exon 11 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1043C>T	p.Pro348Leu	missense_variant	Exon 11 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.989C>T	p.Pro330Leu	missense_variant	Exon 11 of 17	5		ENSP00000296288.5
BAP1	ENST00000490804.1	n.471C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 348 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BAP1-related disorders in the literature. This variant has not been identified 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. -

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P348L variant (also known as c.1043C>T), located in coding exon 11 of the BAP1 gene, results from a C to T substitution at nucleotide position 1043. The proline at codon 348 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.14	N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.052
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.0080	B;.
Vest4		0.41
MutPred		0.27		Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.71
MPC		0.38
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.059
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553645286; hg19: chr3-52439199;