rs146696590

chr4-43030452-G-Achr4-43030452-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2 PP3 BP4_Moderate BP6 BS1

The NM_001080476.3(GRXCR1):c.785G>A(p.Arg262Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000679 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 9.51

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.082303464).
• BP6: Variant 4-43030452-G-A is Benign according to our data. Variant chr4-43030452-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228734.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000611 (93/152110) while in subpopulation NFE AF= 0.000971 (66/67996). AF 95% confidence interval is 0.000782. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRXCR1	NM_001080476.3	c.785G>A	p.Arg262Gln	missense_variant	4/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3	c.785G>A	p.Arg262Gln	missense_variant	4/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151992 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000713 AC: 178 AN: 249478 Hom.: 0 AF XY: 0.000650 AC XY: 88 AN XY: 135350

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000786

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000686 AC: 1003 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.000638 AC XY: 464 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000731

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74356

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000858 Hom.: 0

Bravo AF: 0.000597

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000963 AC: 8

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2017

The p.Arg262Gln variant in GRXCR1 has been identified by our laboratory in 2 ind ividuals with hearing loss; however a second variant was not identified in eithe r individual. The variant has also been identified in 0.4% (36/10150) of Ashkena zi Jewish and 0.1% (102/126588) of European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org/; rs146696590) and has been reported in ClinVar (Variation ID: 228734); however its frequency is not high e nough to rule out a pathogenic role. Computational prediction tools and conserva tion analysis suggest the variant may impact the protein; however this data is i nsufficient to assume pathogenicity. In summary, the clinical significance of th e p.Arg262Gln variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 25 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

GRXCR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.023	D
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.87
MVP		0.47
MPC		0.28
ClinPred		0.092	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.60

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: rs146696590; hg19: chr4-43032469; COSMIC: COSV67669808;