3-52402834-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_004656.4(BAP1):ā€‹c.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

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.49
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 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
BAP1NM_004656.4 linkuse as main transcriptc.1928T>C p.Ile643Thr missense_variant 15/17 ENST00000460680.6 NP_004647.1 Q92560A0A024R305

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BAP1ENST00000460680.6 linkuse as main transcriptc.1928T>C p.Ile643Thr missense_variant 15/171 NM_004656.4 ENSP00000417132.1 Q92560

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461890
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 28, 2023This 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 submitterclinical testingBaylor GeneticsNov 19, 2023- -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 29, 2020This 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 submitterclinical testingAmbry GeneticsJul 19, 2024The 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 submitterclinical testingGeneDxNov 14, 2023Not 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 providedclinical testingPreventionGenetics, part of Exact SciencesApr 04, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;.;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.68
D;D;D
MetaSVM
Benign
-0.82
T
MutationAssessor
Pathogenic
3.1
M;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.3
D;D;D
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.0010
B;.;.
Vest4
0.89
MVP
0.71
MPC
1.3
ClinPred
0.98
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
gMVP
0.89

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

LitVar

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

Other links and lift over

dbSNP: rs376519545; hg19: chr3-52436850; COSMIC: COSV56231572; COSMIC: COSV56231572; API