4-42893406-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr4-42893406-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
GRXCR1	NM_001080476.3	c.140C>T	p.Ala47Val	missense_variant	1/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3	c.140C>T	p.Ala47Val	missense_variant	1/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12856 AN: 151934 Hom.: 955 Cov.: 32

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

GnomAD3 exomes AF: 0.123 AC: 30647 AN: 249146 Hom.: 3292 AF XY: 0.125 AC XY: 16869 AN XY: 135160

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 SAS exome AF: 0.256

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.: 34 AF XY: 0.0866 AC XY: 62949 AN XY: 727094

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.0427

Gnomad4 EAS exome AF: 0.319

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.0587

Gnomad4 OTH exome AF: 0.0933

GnomAD4 genome AF: 0.0847 AC: 12875 AN: 152052 Hom.: 952 Cov.: 32 AF XY: 0.0903 AC XY: 6710 AN XY: 74298

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0593

Gnomad4 OTH AF: 0.0843

Alfa AF: 0.0744 Hom.: 1105

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.28	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.035
Sift	Benign	0.18	T
Sift4G	Benign	0.54	T
Polyphen		0.075	B
Vest4		0.21
MPC		0.046
ClinPred		0.0056	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs57655409; hg19: chr4-42895423; COSMIC: COSV67670153; COSMIC: COSV67670153;