9-114424432-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015404.4(WHRN):c.1318G>A(p.Ala440Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,244 control chromosomes in the GnomAD database, including 46,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A440A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 3635 hom., cov: 32)

Exomes 𝑓: 0.23 ( 42613 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.58

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030617118).

BP6

Variant 9-114424432-C-T is Benign according to our data. Variant chr9-114424432-C-T is described in ClinVar as Benign. ClinVar VariationId is 45647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.1318G>A	p.Ala440Thr	missense_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.1318G>A	p.Ala440Thr	missense_variant	Exon 6 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30683

AN:

152040

Hom.:

3627

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0790

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.227

Gnomad OTH

AF:

0.221

GnomAD2 exomes

AF:

0.262

AC:

65724

AN:

251210

AF XY:

0.257

show subpopulations

Gnomad AFR exome

AF:

0.0744

Gnomad AMR exome

AF:

0.425

Gnomad ASJ exome

AF:

0.228

Gnomad EAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.241

GnomAD4 exome

AF:

0.235

AC:

343333

AN:

1461086

Hom.:

42613

Cov.:

AF XY:

0.236

AC XY:

171366

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.0696

AC:

2328

AN:

33462

American (AMR)

AF:

0.411

AC:

18357

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6053

AN:

26134

East Asian (EAS)

AF:

0.358

AC:

14212

AN:

39698

South Asian (SAS)

AF:

0.274

AC:

23590

AN:

86220

European-Finnish (FIN)

AF:

0.268

AC:

14331

AN:

53412

Middle Eastern (MID)

AF:

0.219

AC:

1147

AN:

5226

European-Non Finnish (NFE)

AF:

0.225

AC:

249636

AN:

1111886

Other (OTH)

AF:

0.227

AC:

13679

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

15024

30049

45073

60098

75122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8750

17500

26250

35000

43750

<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:

0.202

AC:

30714

AN:

152158

Hom.:

3635

Cov.:

AF XY:

0.205

AC XY:

15251

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0789

AC:

3278

AN:

41544

American (AMR)

AF:

0.299

AC:

4567

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

843

AN:

3470

East Asian (EAS)

AF:

0.326

AC:

1682

AN:

5156

South Asian (SAS)

AF:

0.270

AC:

1301

AN:

4818

European-Finnish (FIN)

AF:

0.274

AC:

2908

AN:

10594

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.227

AC:

15434

AN:

67980

Other (OTH)

AF:

0.218

AC:

460

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1208

2416

3625

4833

6041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.219

Hom.:

13104

Bravo

AF:

0.201

TwinsUK

AF:

0.226

AC:

839

ALSPAC

AF:

0.248

AC:

955

ESP6500AA

AF:

0.0831

AC:

366

ESP6500EA

AF:

0.230

AC:

1975

ExAC

AF:

0.252

AC:

30629

Asia WGS

AF:

0.245

AC:

849

AN:

3478

EpiCase

AF:

0.224

EpiControl

AF:

0.221

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 11, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2016

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:2

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2D

Benign:1

Jan 12, 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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

.;.;L

PhyloP100

2.6

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.78

N;N;N

REVEL

Benign

0.023

Sift

Benign

0.097

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0060, 0.0070

.;B;B

Vest4

0.12

MPC

0.12

ClinPred

0.0057

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.022

gMVP

0.20

Mutation Taster

=96/4

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