rs201002003

Positions:

• chr4-42893597-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001080476.3(GRXCR1):​c.331T>C​(p.Tyr111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,613,570 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.25

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 Uncertain_significance. Variant got 0 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054615974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRXCR1	NM_001080476.3	c.331T>C	p.Tyr111His	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	c.331T>C	p.Tyr111His	missense_variant	1/4	1	NM_001080476.3	ENSP00000382670	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 248592 Hom.: 0 AF XY: 0.0000890 AC XY: 12 AN XY: 134854

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000260 AC: 380 AN: 1461468 Hom.: 0 Cov.: 33 AF XY: 0.000241 AC XY: 175 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152102 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74288

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000436

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 111 of the GRXCR1 protein (p.Tyr111His). This variant is present in population databases (rs201002003, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GRXCR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 348818). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Tyr111His var iant in GRXCR1 has not been previously reported in individuals with hearing loss . It has been identified in 27/125910 European chromosomes by the genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs201002003); ho wever this frequency is not high enough to rule out a pathogenic role. The varia nt has also been reported in ClinVar (Variation ID: 348818). The Tyrosine (Tyr) at position 111 is conserved through mammals, but is not highly conserved in evo lutionary distant species with >30 species carry a Histidine (His) at this posit ion, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest the variant may not impact the protein. In summary, while the clinical significance of the p.Tyr111His variant is uncertain, these data suggest that it is more likely to be benign. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.84	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.10
Sift	Benign	0.22	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.16
MPC		0.041
ClinPred		0.046	T
GERP RS		4.6
Varity_R		0.054
gMVP		0.67

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: rs201002003; hg19: chr4-42895614;