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rs267606855

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001080476.3(GRXCR1):c.229C>T(p.Gln77Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GRXCR1
NM_001080476.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 3.70
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 Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-42893495-C-T is Pathogenic according to our data. Variant chr4-42893495-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-42893495-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRXCR1NM_001080476.3 linkuse as main transcriptc.229C>T p.Gln77Ter stop_gained 1/4 ENST00000399770.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRXCR1ENST00000399770.3 linkuse as main transcriptc.229C>T p.Gln77Ter stop_gained 1/41 NM_001080476.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461632
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727136
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:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 25 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 12, 2010- -
Pathogenic, no assertion criteria providedresearchNational Institute on Deafness and Communication Disorders, National Institutes of HealthJul 05, 2018- -
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
Cadd
Pathogenic
37
Dann
Uncertain
1.0
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A
Vest4
0.16
GERP RS
5.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs267606855; hg19: chr4-42895512; API