4-43020345-C-G

Variant names:

• chr4-43020345-C-G
• rs606231120
• NM_001080476.3:c.628-9C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080476.3(GRXCR1):​c.628-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRXCR1 NM_001080476.3 intron
• Scores: Splicing: ADA: 0.004885
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 0 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: G2P, Ambry Genetics, 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	NM_001080476.3	MANE Select	c.628-9C>G		intron	N/A	NP_001073945.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	ENST00000399770.3	TSL:1 MANE Select	c.628-9C>G		intron	N/A	ENSP00000382670.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249010 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435124 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 715814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32968

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087830

Other (OTH) AF: 0.0000168 AC: 1 AN: 59454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000149 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.67
PhyloP100		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.080		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: rs606231120; hg19: chr4-43022362;