3-52404485-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4_StrongBP6_Moderate

The NM_004656.4(BAP1):​c.1218G>C​(p.Glu406Asp) 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 Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E406A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

BAP1
NM_004656.4 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.157
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 Likely_benign. Variant got -3 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=0.056361288).
BP6
Variant 3-52404485-C-G is Benign according to our data. Variant chr3-52404485-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1752271.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BAP1NM_004656.4 linkc.1218G>C p.Glu406Asp 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.1218G>C p.Glu406Asp missense_variant Exon 12 of 17 1 NM_004656.4 ENSP00000417132.1 Q92560
BAP1ENST00000296288.9 linkc.1164G>C p.Glu388Asp missense_variant Exon 12 of 17 5 ENSP00000296288.5 F8W6N3
BAP1ENST00000490804.1 linkn.646G>C non_coding_transcript_exon_variant Exon 2 of 3 2
BAP1ENST00000469613.5 linkc.-10G>C upstream_gene_variant 1 ENSP00000418320.1 H7C4V7

Frequencies

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

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1
Dec 13, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
7.7
DANN
Uncertain
0.98
DEOGEN2
Benign
0.025
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.056
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.7
L;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.64
N;N
REVEL
Benign
0.096
Sift
Benign
0.33
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.0
B;.
Vest4
0.21
MutPred
0.14
Gain of glycosylation at Y401 (P = 0);.;
MVP
0.41
MPC
0.34
ClinPred
0.086
T
GERP RS
-2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.029
gMVP
0.15

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: chr3-52438501; API