rs374620220

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_004656.4(BAP1):​c.1148G>T​(p.Arg383Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

BAP1
NM_004656.4 missense

Scores

3
10
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.14
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BAP1NM_004656.4 linkc.1148G>T p.Arg383Leu missense_variant Exon 12 of 17 ENST00000460680.6 NP_004647.1 Q92560A0A024R305

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BAP1ENST00000460680.6 linkc.1148G>T p.Arg383Leu missense_variant Exon 12 of 17 1 NM_004656.4 ENSP00000417132.1 Q92560
BAP1ENST00000296288.9 linkc.1094G>T p.Arg365Leu missense_variant Exon 12 of 17 5 ENSP00000296288.5 F8W6N3
BAP1ENST00000490804.1 linkn.576G>T non_coding_transcript_exon_variant Exon 2 of 3 2
BAP1ENST00000469613.5 linkc.-80G>T upstream_gene_variant 1 ENSP00000418320.1 H7C4V7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Uncertain
0.034
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.071
T;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.081
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.1
N;N
REVEL
Uncertain
0.36
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.038
D;D
Polyphen
0.99
D;.
Vest4
0.82
MutPred
0.53
Loss of methylation at R383 (P = 0.02);.;
MVP
0.81
MPC
1.3
ClinPred
0.99
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.36
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52438571; API