NM_004656.4:c.878C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004656.4(BAP1):​c.878C>A​(p.Pro293Gln) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P293P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

BAP1
NM_004656.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.25
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 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=0.19757754).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BAP1NM_004656.4 linkc.878C>A p.Pro293Gln missense_variant Exon 10 of 17 ENST00000460680.6 NP_004647.1 Q92560A0A024R305

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BAP1ENST00000460680.6 linkc.878C>A p.Pro293Gln missense_variant Exon 10 of 17 1 NM_004656.4 ENSP00000417132.1 Q92560
BAP1ENST00000296288.9 linkc.824C>A p.Pro275Gln missense_variant Exon 10 of 17 5 ENSP00000296288.5 F8W6N3
BAP1ENST00000471532.5 linkn.1045C>A non_coding_transcript_exon_variant Exon 5 of 5 5

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
LINK: link

Submissions by phenotype

BAP1-related tumor predisposition syndrome Uncertain:1
Mar 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with BAP1-related conditions. This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 293 of the BAP1 protein (p.Pro293Gln). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.0016
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.034
T;.
Eigen
Benign
-0.074
Eigen_PC
Benign
0.054
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.2
L;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.90
N;N
REVEL
Benign
0.097
Sift
Uncertain
0.0020
D;D
Sift4G
Benign
0.52
T;T
Polyphen
0.089
B;.
Vest4
0.27
MutPred
0.35
Gain of glycosylation at S289 (P = 0.0164);.;
MVP
0.71
MPC
0.49
ClinPred
0.77
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52439834; API