rs113203706

Positions:

chr4-42893538-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/21 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

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 -18 ACMG points.

PM1

In a chain Glutaredoxin domain-containing cysteine-rich protein 1 (size 289) in uniprot entity GRCR1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001080476.3

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 [Likely_benign]. Clinvar id is 178379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-42893538-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRXCR1	NM_001080476.3 linkuse as main transcript	c.272G>T	p.Gly91Val	missense_variant	1/4	ENST00000399770.3	NP_001073945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3 linkuse as main transcript	c.272G>T	p.Gly91Val	missense_variant	1/4	1	NM_001080476.3	ENSP00000382670	P1

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

GnomAD3 exomes

AF:

0.00464

AC:

1157

AN:

249094

Hom.:

AF XY:

0.00524

AC XY:

708

AN XY:

135116

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 SAS exome

AF:

0.00791

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

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00731

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00820

Gnomad4 FIN exome

AF:

0.00427

Gnomad4 NFE exome

AF:

0.00438

Gnomad4 OTH exome

AF:

0.00596

GnomAD4 genome

AF:

0.00355

AC:

541

AN:

152238

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00504

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00424

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

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2018	This variant is associated with the following publications: (PMID: 20137774, 20137778) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	GRXCR1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Gly91Val in Exon 01 of GRXCR1: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (25/6762) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs113203706). -

GRXCR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2021

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). -

Autosomal recessive nonsyndromic hearing loss 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.1

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

MutationTaster

Benign

1.0

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

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