rs113203706

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080476.3(GRXCR1):c.272G>T(p.Gly91Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,613,854 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 34 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.80

Publications

14 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=0.0068248212).

BP6

Variant 4-42893538-G-T is Benign according to our data. Variant chr4-42893538-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00355 (541/152238) while in subpopulation SAS AF = 0.00808 (39/4824). AF 95% confidence interval is 0.00608. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	NM_001080476.3	MANE Select	c.272G>T	p.Gly91Val	missense	Exon 1 of 4	NP_001073945.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	ENST00000399770.3	TSL:1 MANE Select	c.272G>T	p.Gly91Val	missense	Exon 1 of 4	ENSP00000382670.2

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

542

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00464

AC:

1157

AN:

249094

AF XY:

0.00524

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00716

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00371

Gnomad NFE exome

AF:

0.00548

Gnomad OTH exome

AF:

0.00594

GnomAD4 exome

AF:

0.00449

AC:

6563

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

3453

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33454

American (AMR)

AF:

0.00280

AC:

125

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00731

AC:

191

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00820

AC:

707

AN:

86258

European-Finnish (FIN)

AF:

0.00427

AC:

228

AN:

53414

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00438

AC:

4869

AN:

1111830

Other (OTH)

AF:

0.00596

AC:

360

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

419

838

1256

1675

2094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00355

AC:

541

AN:

152238

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41560

American (AMR)

AF:

0.00504

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00808

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00453

AC:

308

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00425

Hom.:

Bravo

AF:

0.00322

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00124

AC:

ESP6500EA

AF:

0.00383

AC:

ExAC

AF:

0.00506

AC:

612

Asia WGS

AF:

0.00260

AC:

AN:

3476

EpiCase

AF:

0.00611

EpiControl

AF:

0.00646

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal recessive nonsyndromic hearing loss 25 (1)

GRXCR1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.1

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.050

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.44

M_CAP

Benign

0.0079

MetaRNN

Benign

0.0068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.38

REVEL

Benign

0.051

Sift

Benign

0.34

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.19

MVP

0.21

MPC

0.040

ClinPred

0.0040

GERP RS

1.1

Varity_R

0.046

gMVP

0.70

Mutation Taster

=99/1

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over