rs115109161

chr3-52403877-G-Achr3-52403877-G-Cchr3-52403877-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.1268C>T(p.Thr423Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T423K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 where missense usually causes diseases, BAP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.21297088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAP1	NM_004656.4	c.1268C>T	p.Thr423Ile	missense_variant	13/17	ENST00000460680.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAP1	ENST00000460680.6	c.1268C>T	p.Thr423Ile	missense_variant	13/17	1	NM_004656.4	P1
BAP1	ENST00000469613.5	c.44C>T	p.Thr15Ile	missense_variant	2/5	1
BAP1	ENST00000296288.9	c.1214C>T	p.Thr405Ile	missense_variant	13/17	5
BAP1	ENST00000490804.1	n.696C>T		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

BAP1-related tumor predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with BAP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 423 of the BAP1 protein (p.Thr423Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.72	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.083
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.044	B;.
Vest4		0.24
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.68
MPC		0.41
ClinPred		0.27	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs115109161; hg19: chr3-52437893;