4-42893406-C-T

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.140C>T(p.Ala47Val) variant causes a missense change. The variant allele was found at a frequency of 0.0823 in 1,613,614 control chromosomes in the GnomAD database, including 9,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 952 hom., cov: 32)

Exomes 𝑓: 0.082 ( 8588 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.76

Publications

20 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=0.0016952157).

BP6

Variant 4-42893406-C-T is Benign according to our data. Variant chr4-42893406-C-T is described in ClinVar as [Benign]. Clinvar id is 43886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRXCR1	NM_001080476.3 link	c.140C>T	p.Ala47Val	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.140C>T	p.Ala47Val	missense_variant	Exon 1 of 4	1	NM_001080476.3	ENSP00000382670.2		A8MXD5

Frequencies

GnomAD3 genomes

AF:

0.0846

AC:

12856

AN:

151934

Hom.:

955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.334

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0593

Gnomad OTH

AF:

0.0823

GnomAD2 exomes

AF:

0.123

AC:

30647

AN:

249146

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.0556

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.0416

Gnomad EAS exome

AF:

0.347

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.0613

Gnomad OTH exome

AF:

0.0979

GnomAD4 exome

AF:

0.0821

AC:

119993

AN:

1461562

Hom.:

8588

Cov.:

AF XY:

0.0866

AC XY:

62949

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.0584

AC:

1953

AN:

33452

American (AMR)

AF:

0.206

AC:

9218

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1117

AN:

26130

East Asian (EAS)

AF:

0.319

AC:

12679

AN:

39692

South Asian (SAS)

AF:

0.252

AC:

21747

AN:

86256

European-Finnish (FIN)

AF:

0.0320

AC:

1707

AN:

53418

Middle Eastern (MID)

AF:

0.119

AC:

687

AN:

5764

European-Non Finnish (NFE)

AF:

0.0587

AC:

65254

AN:

1111764

Other (OTH)

AF:

0.0933

AC:

5631

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

6293

12585

18878

25170

31463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0847

AC:

12875

AN:

152052

Hom.:

952

Cov.:

AF XY:

0.0903

AC XY:

6710

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0598

AC:

2483

AN:

41490

American (AMR)

AF:

0.164

AC:

2493

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

161

AN:

3470

East Asian (EAS)

AF:

0.334

AC:

1717

AN:

5140

South Asian (SAS)

AF:

0.257

AC:

1239

AN:

4818

European-Finnish (FIN)

AF:

0.0308

AC:

326

AN:

10590

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0593

AC:

4034

AN:

67982

Other (OTH)

AF:

0.0843

AC:

178

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

558

1116

1675

2233

2791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0756

Hom.:

2286

Bravo

AF:

0.0912

TwinsUK

AF:

0.0561

AC:

208

ALSPAC

AF:

0.0669

AC:

258

ESP6500AA

AF:

0.0537

AC:

213

ESP6500EA

AF:

0.0584

AC:

488

ExAC

AF:

0.120

AC:

14456

Asia WGS

AF:

0.264

AC:

914

AN:

3476

EpiCase

AF:

0.0598

EpiControl

AF:

0.0616

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

Ala47Val in Exon 01 of GRXCR1: This variant is not expected to have clinical sig nificance because it has been identified in 5.7% (386/6772) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs57655409). -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.12

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

Eigen

Benign

-0.021

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

PhyloP100

5.8

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.89

REVEL

Benign

0.035

Sift

Benign

0.18

Sift4G

Benign

0.54

Polyphen

0.075

Vest4

0.21

MPC

0.046

ClinPred

0.0056

GERP RS

5.7

Varity_R

0.14

gMVP

0.37

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

4-42893406-C-T

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