rs4979387

Variant names:

• chr9-114424397-A-G
• rs4979387
• NM_015404.4:c.1353T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-114424397-A-G
• chr9-114424397-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015404.4(WHRN):​c.1353T>C​(p.Gly451Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,612,494 control chromosomes in the GnomAD database, including 480,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45140 hom., cov: 32)
  • Exomes 𝑓: 0.77 (434863 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.78

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-114424397-A-G is Benign according to our data. Variant chr9-114424397-A-G is described in ClinVar as [Benign]. Clinvar id is 45650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114424397-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1353T>C	p.Gly451Gly	synonymous_variant	Exon 6 of 12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1353T>C	p.Gly451Gly	synonymous_variant	Exon 6 of 12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116820 AN: 151990 Hom.: 45082 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.864

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.769

GnomAD3 exomes AF: 0.795 AC: 199862 AN: 251314 Hom.: 80233 AF XY: 0.794 AC XY: 107877 AN XY: 135850

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.781

Gnomad EAS exome AF: 0.938

Gnomad SAS exome AF: 0.867

Gnomad FIN exome AF: 0.681

Gnomad NFE exome AF: 0.754

Gnomad OTH exome AF: 0.781

GnomAD4 exome AF: 0.770 AC: 1124391 AN: 1460386 Hom.: 434863 Cov.: 79 AF XY: 0.771 AC XY: 560394 AN XY: 726488

Gnomad4 AFR exome AF: 0.778

Gnomad4 AMR exome AF: 0.875

Gnomad4 ASJ exome AF: 0.778

Gnomad4 EAS exome AF: 0.954

Gnomad4 SAS exome AF: 0.864

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.755

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.769 AC: 116932 AN: 152108 Hom.: 45140 Cov.: 32 AF XY: 0.768 AC XY: 57100 AN XY: 74356

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.817

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.941

Gnomad4 SAS AF: 0.865

Gnomad4 FIN AF: 0.668

Gnomad4 NFE AF: 0.749

Gnomad4 OTH AF: 0.772

Alfa AF: 0.762 Hom.: 27966

Bravo AF: 0.785

Asia WGS AF: 0.894 AC: 3108 AN: 3478

EpiCase AF: 0.754

EpiControl AF: 0.752

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 2D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.074
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs4979387; hg19: chr9-117186677; COSMIC: COSV54328495;