9-114423486-G-A

Position:

chr9-114423486-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015404.4(WHRN):c.1454C>T(p.Pro485Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,612,330 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P485S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0031 ( 21 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 9.08

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008380979).

BP6

Variant 9-114423486-G-A is Benign according to our data. Variant chr9-114423486-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45654.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=1}. Variant chr9-114423486-G-A is described in Lovd as [Benign]. Variant chr9-114423486-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00354 (539/152210) while in subpopulation NFE AF= 0.00243 (165/68004). AF 95% confidence interval is 0.00212. There are 6 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1454C>T	p.Pro485Leu	missense_variant	7/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1454C>T	p.Pro485Leu	missense_variant	7/12	1	NM_015404.4	P1	Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00370

AC:

927

AN:

250862

Hom.:

AF XY:

0.00371

AC XY:

503

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.00316

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00310

AC:

4527

AN:

1460120

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

2278

AN XY:

725970

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00363

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00274

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152210

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

339

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0265

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00156

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00338

AC:

410

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	WHRN: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2011	Pro485Leu in exon 7 of DFNB31: This variant is not expected to have clinical sig nificance because it has been identified in 6/193 (3.1%) of Caucasian North Amer ican control chromosomes (rs79572315). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 2D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

.;.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

.;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0090

D;D;D

Sift4G

Benign

0.20

T;T;T

Polyphen

1.0, 1.0

.;D;D

Vest4

0.77

MVP

0.52

MPC

0.51

ClinPred

0.021

GERP RS

4.4

Varity_R

0.37

gMVP

0.53

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