4-42893379-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PS1_Moderate PM2 BP4_Strong

The NM_001080476.3(GRXCR1):c.113C>T(p.Pro38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,648 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.48

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.

• PS1: Transcript NM_001080476.3 (GRXCR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057484686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRXCR1	NM_001080476.3	c.113C>T	p.Pro38Leu	missense_variant	1/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3	c.113C>T	p.Pro38Leu	missense_variant	1/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 249104 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461596 Hom.: 1 Cov.: 33 AF XY: 0.000127 AC XY: 92 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000546

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 38 of the GRXCR1 protein (p.Pro38Leu). This variant is present in population databases (rs367784906, gnomAD 0.03%). This missense change has been observed in individual(s) with GRXCR1-related conditions (PMID: 20137774). ClinVar contains an entry for this variant (Variation ID: 498748). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.053
Sift	Benign	0.068	T
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.29
MPC		0.036
ClinPred		0.068	T
GERP RS		4.7
Varity_R		0.056
gMVP		0.50

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: rs367784906; hg19: chr4-42895396; COSMIC: COSV104433309; COSMIC: COSV104433309;