rs1553644988

Positions:

• chr3-52403848-C-G
• chr3-52403848-C-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.1297G>C​(p.Ala433Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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, single submitter U:1
• Conservation: PhyloP100: 1.36

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BAP1. . Gene score misZ 2.6442 (greater than the threshold 3.09). Trascript score misZ 3.2667 (greater than threshold 3.09). GenCC has associacion of gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12539214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1297G>C	p.Ala433Pro	missense_variant	13/17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1297G>C	p.Ala433Pro	missense_variant	13/17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000469613.5	c.70G>C	p.Ala24Pro	missense_variant	2/5	1		ENSP00000418320.1
BAP1	ENST00000296288.9	c.1243G>C	p.Ala415Pro	missense_variant	13/17	5		ENSP00000296288.5
BAP1	ENST00000490804.1	n.725G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

This missense variant replaces alanine with proline at codon 433 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.066
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.010	B;.
Vest4		0.32
MutPred		0.090		Gain of glycosylation at S432 (P = 0.0688);.;
MVP		0.70
MPC		0.53
ClinPred		0.14	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1553644988; hg19: chr3-52437864;