chr4-42893306-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001080476.3(GRXCR1):​c.40C>T​(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34805855).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRXCR1NM_001080476.3 linkuse as main transcriptc.40C>T p.Arg14Trp missense_variant 1/4 ENST00000399770.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRXCR1ENST00000399770.3 linkuse as main transcriptc.40C>T p.Arg14Trp missense_variant 1/41 NM_001080476.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000944
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000402
AC:
10
AN:
248858
Hom.:
0
AF XY:
0.0000519
AC XY:
7
AN XY:
134982
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000486
AC:
71
AN:
1461474
Hom.:
0
Cov.:
33
AF XY:
0.0000523
AC XY:
38
AN XY:
727054
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000247
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 19, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1520485). This variant has not been reported in the literature in individuals affected with GRXCR1-related conditions. This variant is present in population databases (rs201948629, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the GRXCR1 protein (p.Arg14Trp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T
Eigen
Uncertain
0.26
Eigen_PC
Benign
0.17
FATHMM_MKL
Benign
0.26
N
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.081
D
MetaRNN
Benign
0.35
T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
0.97
L
MutationTaster
Benign
0.80
D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.15
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.40
MVP
0.51
MPC
0.24
ClinPred
0.28
T
GERP RS
4.8
Varity_R
0.26
gMVP
0.77

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

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

Other links and lift over

dbSNP: rs201948629; hg19: chr4-42895323; COSMIC: COSV101295579; COSMIC: COSV101295579; API