4-42893123-G-A

Variant names:

• chr4-42893123-G-A
• rs11947487
• NM_001080476.3:c.-144G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001080476.3(GRXCR1):​c.-144G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 880,506 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (11 hom.)
• Consequence: GRXCR1 NM_001080476.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.14
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 4-42893123-G-A is Benign according to our data. Variant chr4-42893123-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1196127.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00747 (1136/152130) while in subpopulation AFR AF = 0.0255 (1058/41530). AF 95% confidence interval is 0.0242. There are 12 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.-144G>A		5_prime_UTR	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.-144G>A		5_prime_UTR	Exon 1 of 4	ENSP00000382670.2	A8MXD5

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1137 AN: 152012 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00764

GnomAD4 exome AF: 0.000869 AC: 633 AN: 728376 Hom.: 11 AF XY: 0.000731 AC XY: 282 AN XY: 385828

African (AFR) AF: 0.0234 AC: 448 AN: 19154

American (AMR) AF: 0.00144 AC: 58 AN: 40352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.000210 AC: 14 AN: 66694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49422

Middle Eastern (MID) AF: 0.00225 AC: 6 AN: 2670

European-Non Finnish (NFE) AF: 0.0000938 AC: 43 AN: 458300

Other (OTH) AF: 0.00178 AC: 64 AN: 35912

GnomAD4 genome AF: 0.00747 AC: 1136 AN: 152130 Hom.: 12 Cov.: 32 AF XY: 0.00729 AC XY: 542 AN XY: 74380

African (AFR) AF: 0.0255 AC: 1058 AN: 41530

American (AMR) AF: 0.00360 AC: 55 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67972

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00861 Hom.: 0

Bravo AF: 0.00830

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.55
PhyloP100		2.1
PromoterAI		-0.0031	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11947487; hg19: chr4-42895140;