chr3-52409554-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS2_Supporting

The NM_004656.4(BAP1):ā€‹c.122G>Cā€‹(p.Gly41Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

BAP1
NM_004656.4 missense, splice_region

Scores

2
7
10
Splicing: ADA: 0.9999
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.70
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 0 ACMG points.

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). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BAP1NM_004656.4 linkc.122G>C p.Gly41Ala missense_variant, splice_region_variant 3/17 ENST00000460680.6 NP_004647.1 Q92560A0A024R305

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BAP1ENST00000460680.6 linkc.122G>C p.Gly41Ala missense_variant, splice_region_variant 3/171 NM_004656.4 ENSP00000417132.1 Q92560

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461876
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

BAP1-related tumor predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 05, 2024This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 41 of the BAP1 protein (p.Gly41Ala). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539927). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2021The p.G41A variant (also known as c.122G>C), located in coding exon 3 of the BAP1 gene, results from a G to C substitution at nucleotide position 122. The amino acid change results in glycine to alanine at codon 41, an amino acid with similar properties. This change occurs in the last base pair of coding exon 3, however, in silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Benign
-0.066
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.6
D;D
REVEL
Benign
0.23
Sift
Benign
0.080
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.20
B;.
Vest4
0.36
MutPred
0.38
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.71
MPC
2.2
ClinPred
0.99
D
GERP RS
4.8
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.50
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553646278; hg19: chr3-52443570; API