4-42893456-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_Moderate BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080476.3(GRXCR1):c.190G>A(p.Gly64Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,890 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G64D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.71

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 -18 ACMG points.

• PS1: Transcript NM_001080476.3 (GRXCR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.0072055757).
• BP6: Variant 4-42893456-G-A is Benign according to our data. Variant chr4-42893456-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1297902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000236 (36/152246) while in subpopulation SAS AF= 0.00746 (36/4824). AF 95% confidence interval is 0.00554. There are 1 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRXCR1	NM_001080476.3	c.190G>A	p.Gly64Ser	missense_variant	1/4	ENST00000399770.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRXCR1	ENST00000399770.3	c.190G>A	p.Gly64Ser	missense_variant	1/4	1	NM_001080476.3	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152128 Hom.: 0 Cov.: 32

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: 0.00746

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000883 AC: 220 AN: 249230 Hom.: 2 AF XY: 0.00114 AC XY: 154 AN XY: 135202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000412 AC: 602 AN: 1461644 Hom.: 8 Cov.: 33 AF XY: 0.000583 AC XY: 424 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000416 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 21, 2023	- -

GRXCR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.20
Sift	Benign	0.23	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.18		Gain of glycosylation at S68 (P = 0.0355);
MVP		0.46
MPC		0.26
ClinPred		0.20	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.64

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

Other links and lift over

dbSNP: rs370551174; hg19: chr4-42895473;