4-83462870-TCTC-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PM4_SupportingBP6
The NM_139076.3(ABRAXAS1):c.826_828del(p.Glu276del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000684 in 1,597,370 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 1 hom. )
Consequence
ABRAXAS1
NM_139076.3 inframe_deletion
NM_139076.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.39
Genes affected
ABRAXAS1 (HGNC:25829): (abraxas 1, BRCA1 A complex subunit) This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_139076.3. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 4-83462870-TCTC-T is Benign according to our data. Variant chr4-83462870-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241860.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABRAXAS1 | NM_139076.3 | c.826_828del | p.Glu276del | inframe_deletion | 9/9 | ENST00000321945.12 | |
ABRAXAS1 | NM_001345962.2 | c.499_501del | p.Glu167del | inframe_deletion | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABRAXAS1 | ENST00000321945.12 | c.826_828del | p.Glu276del | inframe_deletion | 9/9 | 1 | NM_139076.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000189 AC: 44AN: 232672Hom.: 0 AF XY: 0.000190 AC XY: 24AN XY: 126084
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GnomAD4 exome AF: 0.000727 AC: 1051AN: 1445148Hom.: 1 AF XY: 0.000724 AC XY: 520AN XY: 718106
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GnomAD4 genome AF: 0.000276 AC: 42AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This variant, c.826_828del, results in the deletion of 1 amino acid(s) of the ABRAXAS1 protein (p.Glu276del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748475674, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with breast cancer (PMID: 27270457). ClinVar contains an entry for this variant (Variation ID: 241860). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2023 | Variant summary: FAM175A c.826_828delGAG (p.Glu276del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00019 in 234902 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in FAM175A causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin.c.826_828delGAG has been reported in the literature in an individual affected with breast cancer and also in the control cohort (Renault _2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at