rs1553645109
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The ENST00000460680.6(BAP1):βc.1214_1225delβ(p.Glu405_Asp408del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000186 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. E405E) has been classified as Likely benign.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
BAP1
ENST00000460680.6 inframe_deletion
ENST00000460680.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.90
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 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in ENST00000460680.6.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BAP1 | NM_004656.4 | c.1214_1225del | p.Glu405_Asp408del | inframe_deletion | 12/17 | ENST00000460680.6 | NP_004647.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BAP1 | ENST00000460680.6 | c.1214_1225del | p.Glu405_Asp408del | inframe_deletion | 12/17 | 1 | NM_004656.4 | ENSP00000417132 | P1 | |
| BAP1 | ENST00000296288.9 | c.1160_1171del | p.Glu387_Asp390del | inframe_deletion | 12/17 | 5 | ENSP00000296288 | |||
| BAP1 | ENST00000490804.1 | n.642_653del | non_coding_transcript_exon_variant | 2/3 | 2 | |||||
| BAP1 | ENST00000469613.5 | upstream_gene_variant | 1 | ENSP00000418320 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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GnomAD4 genome 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
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 | Sep 17, 2022 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 472662). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1214_1225del, results in the deletion of 4 amino acid(s) of the BAP1 protein (p.Glu405_Asp408del), but otherwise preserves the integrity of the reading frame. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 26, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2021 | The c.1214_1225del12 variant (also known as p.E405_D408del) is located in coding exon 12 of the BAP1 gene. This variant results from an in-frame AGGAGGATGACG deletion at nucleotide positions 1214 to 1225. This results in the in-frame deletion of four amino acid residues at codons 405 to 408. These amino acid positions are not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (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 | Mar 18, 2019 | - - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at