4-42893421-T-G

Variant names:

• chr4-42893421-T-G
• rs780773643
• NM_001080476.3:c.155T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001080476.3(GRXCR1):​c.155T>G​(p.Ile52Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Glutaredoxin domain-containing cysteine-rich protein 1 (size 289) in uniprot entity GRCR1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001080476.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06107071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRXCR1	NM_001080476.3	c.155T>G	p.Ile52Arg	missense_variant	Exon 1 of 4	ENST00000399770.3	NP_001073945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3	c.155T>G	p.Ile52Arg	missense_variant	Exon 1 of 4	1	NM_001080476.3	ENSP00000382670.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152050 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: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461636 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.046
Sift	Benign	0.76	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.26		Gain of glycosylation at S48 (P = 0.028);
MVP		0.23
MPC		0.051
ClinPred		0.20	T
GERP RS		2.7
Varity_R		0.076
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780773643; hg19: chr4-42895438;