chr4-42893291-G-A

Position:

chr4-42893291-G-A

Variant summary

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

The NM_001080476.3(GRXCR1):c.25G>A(p.Glu9Lys) variant causes a missense change. The variant allele was found at a frequency of 0.083 in 1,613,502 control chromosomes in the GnomAD database, including 6,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1313 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5365 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.19

Variant links:

Genes affected

GRXCR1 (HGNC:31673): (glutaredoxin and cysteine rich domain containing 1) This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

GRXCR1 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=0.0017417669).

BP6

Variant 4-42893291-G-A is Benign according to our data. Variant chr4-42893291-G-A is described in ClinVar as [Benign]. Clinvar id is 43887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-42893291-G-A is described in Lovd as [Benign]. Variant chr4-42893291-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRXCR1	NM_001080476.3 linkuse as main transcript	c.25G>A	p.Glu9Lys	missense_variant	1/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3 linkuse as main transcript	c.25G>A	p.Glu9Lys	missense_variant	1/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17855

AN:

151968

Hom.:

1311

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0746

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.0475

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0781

Gnomad OTH

AF:

0.0990

GnomAD3 exomes

AF:

0.0878

AC:

21840

AN:

248822

Hom.:

1182

AF XY:

0.0832

AC XY:

11235

AN XY:

134978

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.0569

Gnomad ASJ exome

AF:

0.0565

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.0427

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.0750

Gnomad OTH exome

AF:

0.0797

GnomAD4 exome

AF:

0.0795

AC:

116123

AN:

1461416

Hom.:

5365

Cov.:

AF XY:

0.0780

AC XY:

56717

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.210

Gnomad4 AMR exome

AF:

0.0566

Gnomad4 ASJ exome

AF:

0.0569

Gnomad4 EAS exome

AF:

0.154

Gnomad4 SAS exome

AF:

0.0431

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.0739

Gnomad4 OTH exome

AF:

0.0865

GnomAD4 genome

AF:

0.117

AC:

17868

AN:

152086

Hom.:

1313

Cov.:

AF XY:

0.118

AC XY:

8804

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.202

Gnomad4 AMR

AF:

0.0745

Gnomad4 ASJ

AF:

0.0550

Gnomad4 EAS

AF:

0.163

Gnomad4 SAS

AF:

0.0475

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.0781

Gnomad4 OTH

AF:

0.0994

Alfa

AF:

0.0864

Hom.:

1065

Bravo

AF:

0.117

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0721

AC:

278

ESP6500AA

AF:

0.180

AC:

732

ESP6500EA

AF:

0.0656

AC:

548

ExAC

AF:

0.0882

AC:

10669

Asia WGS

AF:

0.128

AC:

443

AN:

3478

EpiCase

AF:

0.0727

EpiControl

AF:

0.0658

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Glu9Lys in Exon 01 of GRXCR1: This variant is not expected to have clinical sign ificance because it has been identified in 18.3% (620/3384) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs78136490). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.053

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.0022

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.73

REVEL

Benign

0.051

Sift

Uncertain

0.024

Sift4G

Benign

0.72

Polyphen

0.15

Vest4

0.14

MPC

0.040

ClinPred

0.015

GERP RS

5.0

Varity_R

0.089

gMVP

0.42

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