3-52408080-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The ENST00000460680.6(BAP1):c.256-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,602,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000460680.6 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.256-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000460680.6 | NP_004647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.256-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004656.4 | ENSP00000417132 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000436 AC: 1AN: 229130Hom.: 0 AF XY: 0.00000809 AC XY: 1AN XY: 123632
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1449922Hom.: 0 Cov.: 32 AF XY: 0.00000694 AC XY: 5AN XY: 719966
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
BAP1-related tumor predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | This sequence change falls in intron 4 of the BAP1 gene. It does not directly change the encoded amino acid sequence of the BAP1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD 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: 472695). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). 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 | Jan 10, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 09, 2021 | This variant causes a C to A nucleotide substitution at the -3 position of intron 4 of the BAP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/30944 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. - |
Ewing sarcoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 24, 2017 | This is a splice site alteration in which a C is replaced by an A in intron 4, three nucleotides upstream of exon 5. Classification criteria: PVS1 (Although this alteration is not in a canonical +/- 1 or 2 splice site, examination of the patient's paired tumor transcriptome data revealed that this alteration is associated with abberant splicing and intron retention), PM2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at