3-52406279-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BP6
The NM_004656.4(BAP1):c.757C>A(p.Gln253Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q253R) has been classified as Uncertain significance.
Frequency
Consequence
NM_004656.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.757C>A | p.Gln253Lys | missense_variant | 9/17 | ENST00000460680.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.757C>A | p.Gln253Lys | missense_variant | 9/17 | 1 | NM_004656.4 | P1 | |
BAP1 | ENST00000296288.9 | c.703C>A | p.Gln235Lys | missense_variant | 9/17 | 5 | |||
BAP1 | ENST00000471532.5 | n.924C>A | non_coding_transcript_exon_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251308Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135876
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461838Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727216
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 28, 2021 | This missense variant replaces glutamine with lysine at codon 253 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). An experimental functional study demonstrated this variant had no little to no impact on BAP1 deubiquitinase activity or interaction with the ASXL2 protein (PMID: 26416890). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251308 chromosomes 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2022 | 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. - |
BAP1-related tumor predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2023 | This variant has not been reported in the literature in individuals affected with BAP1-related conditions. This variant is present in population databases (rs776240891, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 253 of the BAP1 protein (p.Gln253Lys). ClinVar contains an entry for this variant (Variation ID: 850655). 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 not 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at