4-42893497-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_001080476.3(GRXCR1):​c.231G>T​(p.Gln77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.260
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.065238774).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GRXCR1NM_001080476.3 linkc.231G>T p.Gln77His missense_variant 1/4 ENST00000399770.3 NP_001073945.1 A8MXD5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GRXCR1ENST00000399770.3 linkc.231G>T p.Gln77His missense_variant 1/41 NM_001080476.3 ENSP00000382670.2 A8MXD5

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249306
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135234
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461634
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.000244
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 19, 2024In silico analysis indicates 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 22, 2024This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the GRXCR1 protein (p.Gln77His). This variant is present in population databases (rs368876169, gnomAD 0.008%). 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: 504593). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GRXCR1 protein function with a negative predictive value of 80%. 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 09, 2016The p.Gln77His variant in GRXCR1 has not been previously reported in individuals with hearing loss. This variant has been identified in 1/4090 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs368876169). Although this variant has been seen in the general pop ulation, its frequency is not high enough to rule out a pathogenic role. Computa tional prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gln77His vari ant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
16
DANN
Uncertain
0.97
DEOGEN2
Benign
0.055
T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.28
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.065
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.83
N
REVEL
Benign
0.050
Sift
Benign
0.12
T
Sift4G
Benign
0.19
T
Polyphen
0.0
B
Vest4
0.26
MutPred
0.21
Loss of sheet (P = 0.0817);
MVP
0.20
MPC
0.051
ClinPred
0.073
T
GERP RS
3.2
Varity_R
0.050
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368876169; hg19: chr4-42895514; API