rs78136490

chr4-42893291-G-Achr4-42893291-G-Cchr4-42893291-G-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.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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.19

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=0.0017417669).
• 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. Variant chr4-42893291-G-A is described in Lovd as [Benign]. Variant chr4-42893291-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
GRXCR1	NM_001080476.3	c.25G>A	p.Glu9Lys	missense_variant	1/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3	c.25G>A	p.Glu9Lys	missense_variant	1/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17855 AN: 151968 Hom.: 1311 Cov.: 32

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

GnomAD3 exomes AF: 0.0878 AC: 21840 AN: 248822 Hom.: 1182 AF XY: 0.0832 AC XY: 11235 AN XY: 134978

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 SAS exome AF: 0.0427

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.: 33 AF XY: 0.0780 AC XY: 56717 AN XY: 727024

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.0566

Gnomad4 ASJ exome AF: 0.0569

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.0431

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.0739

Gnomad4 OTH exome AF: 0.0865

GnomAD4 genome AF: 0.117 AC: 17868 AN: 152086 Hom.: 1313 Cov.: 32 AF XY: 0.118 AC XY: 8804 AN XY: 74342

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0745

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.0475

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.0781

Gnomad4 OTH AF: 0.0994

Alfa AF: 0.0864 Hom.: 1065

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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). -

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	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.053
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.0022	P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.051
Sift	Uncertain	0.024	D
Sift4G	Benign	0.72	T
Polyphen		0.15	B
Vest4		0.14
MPC		0.040
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.089
gMVP		0.42

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

Other links and lift over

dbSNP: rs78136490; hg19: chr4-42895308; COSMIC: COSV67672011; COSMIC: COSV67672011;