rs10213360

Positions:

• chr4-42963142-A-C
• chr4-42963142-A-G
• chr4-42963142-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080476.3(GRXCR1):​c.627+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,611,240 control chromosomes in the GnomAD database, including 514,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53345 hom., cov: 32)
  • Exomes 𝑓: 0.79 (460684 hom.)
• Consequence: GRXCR1 NM_001080476.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002498
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.679

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-42963142-A-C is Benign according to our data. Variant chr4-42963142-A-C is described in ClinVar as [Benign]. Clinvar id is 43888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-42963142-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRXCR1	NM_001080476.3	c.627+8A>C		splice_region_variant, intron_variant		ENST00000399770.3	NP_001073945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3	c.627+8A>C		splice_region_variant, intron_variant		1	NM_001080476.3	ENSP00000382670.2

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126743 AN: 151738 Hom.: 53279 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.986

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.834

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.823

GnomAD3 exomes AF: 0.813 AC: 202327 AN: 248980 Hom.: 83102 AF XY: 0.799 AC XY: 107977 AN XY: 135116

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.701

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.793 AC: 1156803 AN: 1459384 Hom.: 460684 Cov.: 44 AF XY: 0.788 AC XY: 572107 AN XY: 726088

Gnomad4 AFR exome AF: 0.920

Gnomad4 AMR exome AF: 0.893

Gnomad4 ASJ exome AF: 0.718

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.699

Gnomad4 FIN exome AF: 0.827

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.835 AC: 126870 AN: 151856 Hom.: 53345 Cov.: 32 AF XY: 0.837 AC XY: 62133 AN XY: 74202

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.856

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.986

Gnomad4 SAS AF: 0.715

Gnomad4 FIN AF: 0.834

Gnomad4 NFE AF: 0.786

Gnomad4 OTH AF: 0.824

Alfa AF: 0.785 Hom.: 36085

Bravo AF: 0.844

Asia WGS AF: 0.852 AC: 2958 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This 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 submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	627+8A>C in Intron 02 of GRXCR1: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and has been identified in 21.8% (1449/6634) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs10213360). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 25 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs10213360; hg19: chr4-42965159;