rs61733348

Variant names:

• chr4-43030444-C-T
• rs61733348
• NM_001080476.3:c.777C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001080476.3(GRXCR1):​c.777C>T​(p.Ser259Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,613,982 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: GRXCR1 NM_001080476.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.415
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 4-43030444-C-T is Benign according to our data. Variant chr4-43030444-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.415 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2171/152166) while in subpopulation AFR AF = 0.049 (2034/41470). AF 95% confidence interval is 0.0473. There are 51 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

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.777C>T	p.Ser259Ser	synonymous	Exon 4 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.777C>T	p.Ser259Ser	synonymous	Exon 4 of 4	ENSP00000382670.2	A8MXD5

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2170 AN: 152048 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00364 AC: 908 AN: 249480 AF XY: 0.00277

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00145 AC: 2120 AN: 1461816 Hom.: 43 Cov.: 31 AF XY: 0.00125 AC XY: 911 AN XY: 727218

African (AFR) AF: 0.0497 AC: 1663 AN: 33480

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000818 AC: 91 AN: 1111952

Other (OTH) AF: 0.00366 AC: 221 AN: 60392

GnomAD4 genome AF: 0.0143 AC: 2171 AN: 152166 Hom.: 51 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74402

African (AFR) AF: 0.0490 AC: 2034 AN: 41470

American (AMR) AF: 0.00674 AC: 103 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00637 Hom.: 12

Bravo AF: 0.0166

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.76
DANN	Benign	0.63
PhyloP100		0.41
Mutation Taster		=100/0	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: rs61733348; hg19: chr4-43032461;