3-52402834-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_004656.4(BAP1):āc.1928T>Cā(p.Ile643Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
BAP1
NM_004656.4 missense
NM_004656.4 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 7.49
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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). GenCC has associacion of gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.1928T>C | p.Ile643Thr | missense_variant | 15/17 | ENST00000460680.6 | NP_004647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.1928T>C | p.Ile643Thr | missense_variant | 15/17 | 1 | NM_004656.4 | ENSP00000417132.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
Bravo
AF:
ESP6500AA
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ESP6500EA
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1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
BAP1-related tumor predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 28, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 643 of the BAP1 protein (p.Ile643Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple primary cutaneous melanomas (PMID: 31382929). ClinVar contains an entry for this variant (Variation ID: 490825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BAP1 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 19, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 29, 2020 | This missense variant replaces isoleucine with threonine at codon 643 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with multiple primary melanomas (PMID: 31382929). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2024 | The p.I643T variant (also known as c.1928T>C), located in coding exon 15 of the BAP1 gene, results from a T to C substitution at nucleotide position 1928. The isoleucine at codon 643 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with BAP1-related disease (Ambry internal data). This alteration was detected in 21 Italian patients with cutaneous malignant melanoma; however, all individuals were from the same region of Southern Italy and this alteration was also reported to co-occur in multiple samples with variants in other genes that the authors classified as pathogenic (Casula M et al. BMC Cancer, 2019 Aug;19:772). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with cutaneous malignant melanoma; however, many individuals in the study were reported to harbor other pathogenic variants (PMID: 31382929); This variant is associated with the following publications: (PMID: 32028647, 31382929) - |
BAP1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 04, 2024 | The BAP1 c.1928T>C variant is predicted to result in the amino acid substitution p.Ile643Thr. This variant was reported in twenty one individuals with multiple primary melanomas, however all those patients were located in the same geographic region (southern Italy) and some patients carried also other potentially causative variants (Casula et al. 2019. PubMed ID: 31382929). This variant has not been reported in a large population database , indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at