chr4-42893291-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001080476.3(GRXCR1):​c.25G>A​(p.Glu9Lys) variant causes a missense change. The variant allele was found at a frequency of 0.083 in 1,613,502 control chromosomes in the GnomAD database, including 6,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1313 hom., cov: 32)
Exomes 𝑓: 0.079 ( 5365 hom. )

Consequence

GRXCR1
NM_001080476.3 missense

Scores

1
3
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.19
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0017417669).
BP6
Variant 4-42893291-G-A is Benign according to our data. Variant chr4-42893291-G-A is described in ClinVar as [Benign]. Clinvar id is 43887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-42893291-G-A is described in Lovd as [Benign]. Variant chr4-42893291-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRXCR1NM_001080476.3 linkuse as main transcriptc.25G>A p.Glu9Lys missense_variant 1/4 ENST00000399770.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRXCR1ENST00000399770.3 linkuse as main transcriptc.25G>A p.Glu9Lys missense_variant 1/41 NM_001080476.3 P1

Frequencies

GnomAD3 genomes
AF:
0.117
AC:
17855
AN:
151968
Hom.:
1311
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.202
Gnomad AMI
AF:
0.0230
Gnomad AMR
AF:
0.0746
Gnomad ASJ
AF:
0.0550
Gnomad EAS
AF:
0.163
Gnomad SAS
AF:
0.0475
Gnomad FIN
AF:
0.146
Gnomad MID
AF:
0.0538
Gnomad NFE
AF:
0.0781
Gnomad OTH
AF:
0.0990
GnomAD3 exomes
AF:
0.0878
AC:
21840
AN:
248822
Hom.:
1182
AF XY:
0.0832
AC XY:
11235
AN XY:
134978
show subpopulations
Gnomad AFR exome
AF:
0.206
Gnomad AMR exome
AF:
0.0569
Gnomad ASJ exome
AF:
0.0565
Gnomad EAS exome
AF:
0.163
Gnomad SAS exome
AF:
0.0427
Gnomad FIN exome
AF:
0.137
Gnomad NFE exome
AF:
0.0750
Gnomad OTH exome
AF:
0.0797
GnomAD4 exome
AF:
0.0795
AC:
116123
AN:
1461416
Hom.:
5365
Cov.:
33
AF XY:
0.0780
AC XY:
56717
AN XY:
727024
show subpopulations
Gnomad4 AFR exome
AF:
0.210
Gnomad4 AMR exome
AF:
0.0566
Gnomad4 ASJ exome
AF:
0.0569
Gnomad4 EAS exome
AF:
0.154
Gnomad4 SAS exome
AF:
0.0431
Gnomad4 FIN exome
AF:
0.143
Gnomad4 NFE exome
AF:
0.0739
Gnomad4 OTH exome
AF:
0.0865
GnomAD4 genome
AF:
0.117
AC:
17868
AN:
152086
Hom.:
1313
Cov.:
32
AF XY:
0.118
AC XY:
8804
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.202
Gnomad4 AMR
AF:
0.0745
Gnomad4 ASJ
AF:
0.0550
Gnomad4 EAS
AF:
0.163
Gnomad4 SAS
AF:
0.0475
Gnomad4 FIN
AF:
0.146
Gnomad4 NFE
AF:
0.0781
Gnomad4 OTH
AF:
0.0994
Alfa
AF:
0.0864
Hom.:
1065
Bravo
AF:
0.117
TwinsUK
AF:
0.0763
AC:
283
ALSPAC
AF:
0.0721
AC:
278
ESP6500AA
AF:
0.180
AC:
732
ESP6500EA
AF:
0.0656
AC:
548
ExAC
AF:
0.0882
AC:
10669
Asia WGS
AF:
0.128
AC:
443
AN:
3478
EpiCase
AF:
0.0727
EpiControl
AF:
0.0658

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMay 09, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 07, 2012Glu9Lys in Exon 01 of GRXCR1: This variant is not expected to have clinical sign ificance because it has been identified in 18.3% (620/3384) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs78136490). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Autosomal recessive nonsyndromic hearing loss 25 Benign:1
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.065
T
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.053
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.68
T
MetaRNN
Benign
0.0017
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.0022
P
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.73
N
REVEL
Benign
0.051
Sift
Uncertain
0.024
D
Sift4G
Benign
0.72
T
Polyphen
0.15
B
Vest4
0.14
MPC
0.040
ClinPred
0.015
T
GERP RS
5.0
Varity_R
0.089
gMVP
0.42

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: rs78136490; hg19: chr4-42895308; COSMIC: COSV67672011; COSMIC: COSV67672011; API