rs13125836

chr4-83462582-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139076.3(ABRAXAS1):c.1117G>A(p.Asp373Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,614,020 control chromosomes in the GnomAD database, including 2,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D373G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (192 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2217 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025427938).
• BP6: Variant 4-83462582-C-T is Benign according to our data. Variant chr4-83462582-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABRAXAS1	NM_139076.3	c.1117G>A	p.Asp373Asn	missense_variant	9/9	ENST00000321945.12
ABRAXAS1	NM_001345962.2	c.790G>A	p.Asp264Asn	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.1117G>A	p.Asp373Asn	missense_variant	9/9	1	NM_139076.3	P1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6382 AN: 152136 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0968

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0440 AC: 11060 AN: 251372 Hom.: 348 AF XY: 0.0446 AC XY: 6062 AN XY: 135862

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.0836

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0893

Gnomad NFE exome AF: 0.0556

Gnomad OTH exome AF: 0.0587

GnomAD4 exome AF: 0.0513 AC: 75042 AN: 1461766 Hom.: 2217 Cov.: 31 AF XY: 0.0506 AC XY: 36760 AN XY: 727188

Gnomad4 AFR exome AF: 0.00833

Gnomad4 AMR exome AF: 0.0345

Gnomad4 ASJ exome AF: 0.0896

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0839

Gnomad4 NFE exome AF: 0.0560

Gnomad4 OTH exome AF: 0.0459

GnomAD4 genome AF: 0.0419 AC: 6377 AN: 152254 Hom.: 192 Cov.: 33 AF XY: 0.0433 AC XY: 3220 AN XY: 74428

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0456

Gnomad4 ASJ AF: 0.0901

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0968

Gnomad4 NFE AF: 0.0542

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0550 Hom.: 533

Bravo AF: 0.0387

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0536 AC: 461

ExAC AF: 0.0424 AC: 5152

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0629

EpiControl AF: 0.0624

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2014

This alteration is classified as 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. -

ABRAXAS1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneKor MSA

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0040	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.15
Sift	Benign	0.097	T;T
Sift4G	Benign	0.071	T;T
Polyphen		0.99	D;.
Vest4		0.12
MPC		0.40
ClinPred		0.0096	T
GERP RS		5.1
Varity_R		0.093
gMVP		0.15

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

Other links and lift over

dbSNP: rs13125836; hg19: chr4-84383735; COSMIC: COSV55030274; COSMIC: COSV55030274;