4-42893291-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:6

Conservation

PhyloP100: 5.19

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 25
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GRXCR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
GRXCR1	NM_001080476.3 link	c.25G>A	p.Glu9Lys	missense_variant	Exon 1 of 4	ENST00000399770.3	NP_001073945.1	A8MXD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3 link	c.25G>A	p.Glu9Lys	missense_variant	Exon 1 of 4	1	NM_001080476.3	ENSP00000382670.2		A8MXD5

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

GnomAD2 exomes

AF:

0.0878

AC:

21840

AN:

248822

AF XY:

0.0832

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 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

African (AFR)

AF:

0.210

AC:

7017

AN:

33438

American (AMR)

AF:

0.0566

AC:

2529

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0569

AC:

1487

AN:

26122

East Asian (EAS)

AF:

0.154

AC:

6117

AN:

39666

South Asian (SAS)

AF:

0.0431

AC:

3718

AN:

86256

European-Finnish (FIN)

AF:

0.143

AC:

7619

AN:

53416

Middle Eastern (MID)

AF:

0.0459

AC:

264

AN:

5754

European-Non Finnish (NFE)

AF:

0.0739

AC:

82150

AN:

1111724

Other (OTH)

AF:

0.0865

AC:

5222

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6275

12550

18824

25099

31374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.117

AC:

17868

AN:

152086

Hom.:

1313

Cov.:

AF XY:

0.118

AC XY:

8804

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.202

AC:

8371

AN:

41516

American (AMR)

AF:

0.0745

AC:

1138

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3470

East Asian (EAS)

AF:

0.163

AC:

837

AN:

5128

South Asian (SAS)

AF:

0.0475

AC:

229

AN:

4820

European-Finnish (FIN)

AF:

0.146

AC:

1545

AN:

10582

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0781

AC:

5309

AN:

67972

Other (OTH)

AF:

0.0994

AC:

210

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

783

1567

2350

3134

3917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0925

Hom.:

1785

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 25

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

(source)

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

PhyloP100

5.2

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

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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4-42893291-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over