9-114424432-C-T

Position:

chr9-114424432-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 45647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114424432-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1318G>A	p.Ala440Thr	missense_variant	6/12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1318G>A	p.Ala440Thr	missense_variant	6/12	1	NM_015404.4	ENSP00000354623	P1	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

GnomAD3 exomes

AF:

0.262

AC:

65724

AN:

251210

Hom.:

9677

AF XY:

0.257

AC XY:

34927

AN XY:

135818

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 SAS exome

AF:

0.270

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

Gnomad4 AFR exome

AF:

0.0696

Gnomad4 AMR exome

AF:

0.411

Gnomad4 ASJ exome

AF:

0.232

Gnomad4 EAS exome

AF:

0.358

Gnomad4 SAS exome

AF:

0.274

Gnomad4 FIN exome

AF:

0.268

Gnomad4 NFE exome

AF:

0.225

Gnomad4 OTH exome

AF:

0.227

GnomAD4 genome

AF:

0.202

AC:

30714

AN:

152158

Hom.:

3635

Cov.:

AF XY:

0.205

AC XY:

15251

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0789

Gnomad4 AMR

AF:

0.299

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.326

Gnomad4 SAS

AF:

0.270

Gnomad4 FIN

AF:

0.274

Gnomad4 NFE

AF:

0.227

Gnomad4 OTH

AF:

0.218

Alfa

AF:

0.224

Hom.:

9827

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Usher syndrome type 2D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

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

MutationTaster

Benign

0.013

P;P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over