rs4979387

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.78

Publications

27 publications found

Variant links:

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]

WHRN Gene-Disease associations (from GenCC):

Usher syndrome type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
autosomal recessive nonsyndromic hearing loss 31
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WHRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 45650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 link	c.1353T>C	p.Gly451Gly	synonymous_variant	Exon 6 of 12	ENST00000362057.4	NP_056219.3	Q9P202-1B9EGE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 link	c.1353T>C	p.Gly451Gly	synonymous_variant	Exon 6 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116820

AN:

151990

Hom.:

45082

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.795

AC:

199862

AN:

251314

AF XY:

0.794

show subpopulations

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 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.:

AF XY:

0.771

AC XY:

560394

AN XY:

726488

show subpopulations

African (AFR)

AF:

0.778

AC:

26008

AN:

33434

American (AMR)

AF:

0.875

AC:

39125

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.778

AC:

20324

AN:

26134

East Asian (EAS)

AF:

0.954

AC:

37864

AN:

39700

South Asian (SAS)

AF:

0.864

AC:

74497

AN:

86186

European-Finnish (FIN)

AF:

0.688

AC:

36758

AN:

53418

Middle Eastern (MID)

AF:

0.774

AC:

3597

AN:

4646

European-Non Finnish (NFE)

AF:

0.755

AC:

839111

AN:

1111888

Other (OTH)

AF:

0.782

AC:

47107

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

13935

27870

41806

55741

69676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20410

40820

61230

81640

102050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.769

AC:

116932

AN:

152108

Hom.:

45140

Cov.:

AF XY:

0.768

AC XY:

57100

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.774

AC:

32125

AN:

41488

American (AMR)

AF:

0.817

AC:

12501

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.781

AC:

2712

AN:

3472

East Asian (EAS)

AF:

0.941

AC:

4851

AN:

5156

South Asian (SAS)

AF:

0.865

AC:

4172

AN:

4824

European-Finnish (FIN)

AF:

0.668

AC:

7075

AN:

10596

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.749

AC:

50923

AN:

67964

Other (OTH)

AF:

0.772

AC:

1628

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1415

2830

4246

5661

7076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.761

Hom.:

35524

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

LINK: link

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

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.074

(source)

DANN

Benign

0.53

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over