rs1553645128
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_004656.4(BAP1):c.1201_1203delinsGAG(p.Tyr401Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y401C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
BAP1
NM_004656.4 missense
NM_004656.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.36
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 where missense usually causes diseases, BAP1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.1201_1203delinsGAG | p.Tyr401Glu | missense_variant | 12/17 | ENST00000460680.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.1201_1203delinsGAG | p.Tyr401Glu | missense_variant | 12/17 | 1 | NM_004656.4 | P1 | |
BAP1 | ENST00000296288.9 | c.1147_1149delinsGAG | p.Tyr383Glu | missense_variant | 12/17 | 5 | |||
BAP1 | ENST00000490804.1 | n.629_631delinsGAG | non_coding_transcript_exon_variant | 2/3 | 2 | ||||
BAP1 | ENST00000469613.5 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2023 | Observed in a healthy control, but absent from cases, in a melanoma case-control study (O'Shea et al., 2017); Published functional studies demonstrate no damaging effect: deubiquitinase activity comparable to wild-type (O'Shea et al., 2017); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29761599, 30039884, 23056405, 28062663) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.1201_1203delTATinsGAG variant (also known as p.Y401E), located in coding exon 12 of the BAP1 gene, results from an in-frame deletion of TAT and insertion of GAG between nucleotide positions 1201 and 1203. This results in the substitution of the tyrosine residue for the glutamic acid residue at codon 401, an amino acid with dissimilar properties. In one study, this variant was identified in 0/1977 melanoma cases and in 1/754 controls (O'Shea et al. Hum Mol Genet 2017 02;26(4):717-28). Based on data from gnomad, the p.Y401E allele has an overall frequency of approximately 0.014% (39/280040). To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 40000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 17, 2023 | This missense variant replaces tyrosine with glutamic acid at codon 401 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature, but has been reported in an unaffected control in a large melanoma case-control study (PMID: 28062663). 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. - |
BAP1-related tumor predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 401 of the BAP1 protein (p.Tyr401Glu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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: 584648). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change does not substantially affect BAP1 function (PMID: 28062663). 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. - |
BAP1-related tumor predisposition syndrome;C5676925:Kury-Isidor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at