4-42893291-G-A

Variant names:

• chr4-42893291-G-A
• rs78136490
• NM_001080476.3:c.25G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/21 in silico tools predict 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.19
• Publications: 18 publications found

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]

GRXCR1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 43887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	NM_001080476.3	MANE Select	c.25G>A	p.Glu9Lys	missense	Exon 1 of 4	NP_001073945.1	A8MXD5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	ENST00000399770.3	TSL:1 MANE Select	c.25G>A	p.Glu9Lys	missense	Exon 1 of 4	ENSP00000382670.2	A8MXD5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17855 AN: 151968 Hom.: 1311 Cov.: 32

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

GnomAD2 exomes AF: 0.0878 AC: 21840 AN: 248822 AF XY: 0.0832

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 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

African (AFR) AF: 0.210 AC: 7017 AN: 33438

American (AMR) AF: 0.0566 AC: 2529 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1487 AN: 26122

East Asian (EAS) AF: 0.154 AC: 6117 AN: 39666

South Asian (SAS) AF: 0.0431 AC: 3718 AN: 86256

European-Finnish (FIN) AF: 0.143 AC: 7619 AN: 53416

Middle Eastern (MID) AF: 0.0459 AC: 264 AN: 5754

European-Non Finnish (NFE) AF: 0.0739 AC: 82150 AN: 1111724

Other (OTH) AF: 0.0865 AC: 5222 AN: 60370

GnomAD4 genome AF: 0.117 AC: 17868 AN: 152086 Hom.: 1313 Cov.: 32 AF XY: 0.118 AC XY: 8804 AN XY: 74342

African (AFR) AF: 0.202 AC: 8371 AN: 41516

American (AMR) AF: 0.0745 AC: 1138 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.163 AC: 837 AN: 5128

South Asian (SAS) AF: 0.0475 AC: 229 AN: 4820

European-Finnish (FIN) AF: 0.146 AC: 1545 AN: 10582

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0781 AC: 5309 AN: 67972

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.0925 Hom.: 1785

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 25 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.2
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
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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