rs13125836

Positions:

chr4-83462582-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 192 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2217 hom. )

Consequence

ABRAXAS1
NM_139076.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.30

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]

ABRAXAS1 links:

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]

MRPS18C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ABRAXAS1	NM_139076.3 link	c.1117G>A	p.Asp373Asn	missense_variant	9/9	ENST00000321945.12	NP_620775.2	Q6UWZ7-1
ABRAXAS1	NM_001345962.2 link	c.790G>A	p.Asp264Asn	missense_variant	8/8		NP_001332891.1	Q6UWZ7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12 link	c.1117G>A	p.Asp373Asn	missense_variant	9/9	1	NM_139076.3	ENSP00000369857.3		Q6UWZ7-1

Frequencies

GnomAD3 genomes

AF:

0.0419

AC:

6382

AN:

152136

Hom.:

192

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0506

AC XY:

36760

AN XY:

727188

show subpopulations

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.:

AF XY:

0.0433

AC XY:

3220

AN XY:

74428

show subpopulations

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:

ESP6500EA

AF:

0.0536

AC:

461

ExAC

AF:

0.0424

AC:

5152

Asia WGS

AF:

0.00549

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0040

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.34

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over