rs587780262

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_139076.3(ABRAXAS1):​c.1106dupG​(p.Ser370fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

ABRAXAS1
NM_139076.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: -0.419
Variant links:
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]

Genome browser will be placed here

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;
PP5
Variant 4-83462592-T-TC is Pathogenic according to our data. Variant chr4-83462592-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128215.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABRAXAS1NM_139076.3 linkuse as main transcriptc.1106dupG p.Ser370fs frameshift_variant 9/9 ENST00000321945.12 NP_620775.2 Q6UWZ7-1
ABRAXAS1NM_001345962.2 linkuse as main transcriptc.779dupG p.Ser261fs frameshift_variant 8/8 NP_001332891.1 Q6UWZ7-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABRAXAS1ENST00000321945.12 linkuse as main transcriptc.1106dupG p.Ser370fs frameshift_variant 9/91 NM_139076.3 ENSP00000369857.3 Q6UWZ7-1

Frequencies

GnomAD3 genomes
AF:
0.0000525
AC:
8
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251388
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000554
Gnomad NFE exome
AF:
0.0000968
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000465
AC:
68
AN:
1461828
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000374
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152238
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 01, 2020This variant is a single nucleotide duplication in exon 9 of the FAM175A (ABRAXAS1) mRNA (c.1106dupG). This results in a frameshift after codon 370 and the creation of a premature translation stop signal 2 amino acid residues later. This mutation is expected to result in loss of normal protein function through protein truncation, where the phospho-SXXF motif, necessary for interaction with BRCA1 (PMID: 17525340) is lost. This mutation has been reported in 2 ovarian cancer patients (PMID: 24240112 ). The mutation database ClinVar contains entries for this variant (Variation ID: 128215). -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 04, 2020The c.1106dupG variant, located in coding exon 9 of the FAM175A gene, results from a duplication of G at nucleotide position 1106, causing a translational frameshift with a predicted alternate stop codon (p.S370Ifs*2). This alteration has been reported in individuals diagnosed with diffuse glioma and ovarian cancers (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11, Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration is expected to result in loss of function by premature protein truncation as it removes a region of the protein involved in binding of BRCA1 (Liu Z et al. Nat. Struct. Mol. Biol., 2007 Aug;14:716-20, Wang B et al. Science, 2007 May;316:1194-8). However, loss of function of FAM175A has not been clearly established as a mechanism of disease. Based on data from the Genome Aggregation Database (gnomAD), the c.1106dupG allele has a overall frequency of approximately 0.009194% (26/282792). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 18, 2023This sequence change creates a premature translational stop signal (p.Ser370Ilefs*2) in the ABRAXAS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the ABRAXAS1 protein. This variant is present in population databases (rs587780262, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with diffuse glioma, individuals undergoing testing for a personal or family history of breast and/or ovarian cancer, and/or Kaposi sarcoma (PMID: 24240112, 26556299, 31159747, 31361614, 31980526). This variant is also known as FAM175 c.1106dup. ClinVar contains an entry for this variant (Variation ID: 128215). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780262; hg19: chr4-84383745; API