4-42893597-T-C

Variant summary

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

The NM_001080476.3(GRXCR1):ā€‹c.331T>Cā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00016 ( 1 hom., cov: 32)
Exomes š‘“: 0.00026 ( 0 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.25
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=0.054615974).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GRXCR1NM_001080476.3 linkuse as main transcriptc.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
GRXCR1ENST00000399770.3 linkuse as main transcriptc.331T>C p.Tyr111His missense_variant 1/41 NM_001080476.3 ENSP00000382670 P1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152102
Hom.:
1
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 06, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 21, 2021In 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 19, 2022This 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 18, 2017Variant 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

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

Other links and lift over

dbSNP: rs201002003; hg19: chr4-42895614; API