NM_001080476.3:c.140C>T

Variant names:

• chr4-42893406-C-T
• rs57655409
• NM_001080476.3:c.140C>T

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.140C>T​(p.Ala47Val) variant causes a missense change. The variant allele was found at a frequency of 0.0823 in 1,613,614 control chromosomes in the GnomAD database, including 9,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (952 hom., cov: 32)
  • Exomes 𝑓: 0.082 (8588 hom.)
• Consequence: GRXCR1 NM_001080476.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.76
• Publications: 20 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), PanelApp Australia
• 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=0.0016952157).
• BP6: Variant 4-42893406-C-T is Benign according to our data. Variant chr4-42893406-C-T is described in ClinVar as Benign. ClinVar VariationId is 43886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 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.140C>T	p.Ala47Val	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.140C>T	p.Ala47Val	missense	Exon 1 of 4	ENSP00000382670.2	A8MXD5

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12856 AN: 151934 Hom.: 955 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0823

GnomAD2 exomes AF: 0.123 AC: 30647 AN: 249146 AF XY: 0.125

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.347

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0979

GnomAD4 exome AF: 0.0821 AC: 119993 AN: 1461562 Hom.: 8588 Cov.: 34 AF XY: 0.0866 AC XY: 62949 AN XY: 727094

African (AFR) AF: 0.0584 AC: 1953 AN: 33452

American (AMR) AF: 0.206 AC: 9218 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1117 AN: 26130

East Asian (EAS) AF: 0.319 AC: 12679 AN: 39692

South Asian (SAS) AF: 0.252 AC: 21747 AN: 86256

European-Finnish (FIN) AF: 0.0320 AC: 1707 AN: 53418

Middle Eastern (MID) AF: 0.119 AC: 687 AN: 5764

European-Non Finnish (NFE) AF: 0.0587 AC: 65254 AN: 1111764

Other (OTH) AF: 0.0933 AC: 5631 AN: 60382

GnomAD4 genome AF: 0.0847 AC: 12875 AN: 152052 Hom.: 952 Cov.: 32 AF XY: 0.0903 AC XY: 6710 AN XY: 74298

African (AFR) AF: 0.0598 AC: 2483 AN: 41490

American (AMR) AF: 0.164 AC: 2493 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3470

East Asian (EAS) AF: 0.334 AC: 1717 AN: 5140

South Asian (SAS) AF: 0.257 AC: 1239 AN: 4818

European-Finnish (FIN) AF: 0.0308 AC: 326 AN: 10590

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0593 AC: 4034 AN: 67982

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

Alfa AF: 0.0756 Hom.: 2286

Bravo AF: 0.0912

TwinsUK AF: 0.0561 AC: 208

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.0537 AC: 213

ESP6500EA AF: 0.0584 AC: 488

ExAC AF: 0.120 AC: 14456

Asia WGS AF: 0.264 AC: 914 AN: 3476

EpiCase AF: 0.0598

EpiControl AF: 0.0616

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.035
Sift	Benign	0.18	T
Sift4G	Benign	0.54	T
Polyphen		0.075	B
Vest4		0.21
MPC		0.046
ClinPred		0.0056	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.37
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs57655409; hg19: chr4-42895423; COSMIC: COSV67670153; COSMIC: COSV67670153;