rs142990800

Variant summary

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

The NM_015404.4(WHRN):c.1048C>T(p.Arg350Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,613,976 control chromosomes in the GnomAD database, including 3 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. R350Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.29

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=0.011066735).

BP6

Variant 9-114426329-G-A is Benign according to our data. Variant chr9-114426329-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178337.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr9-114426329-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (206/152318) while in subpopulation AFR AF= 0.00481 (200/41558). AF 95% confidence interval is 0.00427. There are 2 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1048C>T	p.Arg350Trp	missense_variant	4/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1048C>T	p.Arg350Trp	missense_variant	4/12	1	NM_015404.4	P1	Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000355

AC:

AN:

250870

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00475

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1461658

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00529

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152318

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000241

Hom.:

Bravo

AF:

0.00132

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	This variant is associated with the following publications: (PMID: 20352026, 30245029) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2017	The p.Arg350Trp variant (rs142990800) has been reported in the medical literature in a single Egyptian individual with Usher syndrome (Aller 2010); however, inheritance and specific clinical information were not reported for this individual. The p.Arg350Trp variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.53% in the African population (identified in 128 out of 23,990 chromosomes; 1 homozygote), and is classified as likely benign in ClinVar (Variant ID: 178337). The arginine at codon 350 is moderately conserved considering 12 species (Alamut software v2.9.0), but computational analyses suggest that this variant affects the WHRN protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). While this variant appears to be a benign polymorphism in the African population, the available evidence is insufficient to classify the clinical significance of this variant with certainty. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Arg350Trp in Exon 04 of DFNB31: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (16/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs142990800). -

WHRN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.029

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.39

MVP

0.61

MPC

0.51

ClinPred

0.069

GERP RS

4.0

Varity_R

0.33

gMVP

0.56

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