rs56204273

Positions:

Variant summary

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

The NM_015404.4(WHRN):c.229A>T(p.Thr77Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00938 in 1,611,512 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0065 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0097 ( 99 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.68

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=0.006608993).

BP6

Variant 9-114504573-T-A is Benign according to our data. Variant chr9-114504573-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45671.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}. Variant chr9-114504573-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00652 (993/152368) while in subpopulation SAS AF= 0.0164 (79/4830). AF 95% confidence interval is 0.0135. There are 9 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.229A>T	p.Thr77Ser	missense_variant	1/12	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.229A>T	p.Thr77Ser	missense_variant	1/12	1	NM_015404.4	ENSP00000354623	P1	Q9P202-1
WHRN	ENST00000374057.3 linkuse as main transcript	c.229A>T	p.Thr77Ser	missense_variant	1/2	2		ENSP00000363170		Q9P202-2
WHRN	ENST00000699486.1 linkuse as main transcript			upstream_gene_variant				ENSP00000514397
WHRN	ENST00000673811.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00652

AC:

993

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00976

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00742

AC:

1789

AN:

241140

Hom.:

AF XY:

0.00823

AC XY:

1082

AN XY:

131486

show subpopulations

Gnomad AFR exome

AF:

0.00146

Gnomad AMR exome

AF:

0.00265

Gnomad ASJ exome

AF:

0.00700

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.00172

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00718

GnomAD4 exome

AF:

0.00968

AC:

14120

AN:

1459144

Hom.:

Cov.:

AF XY:

0.00986

AC XY:

7156

AN XY:

726028

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.00724

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.00158

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00944

GnomAD4 genome

AF:

0.00652

AC:

993

AN:

152368

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

479

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00976

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.00664

Hom.:

Bravo

AF:

0.00620

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00748

AC:

907

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00937

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WHRN: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Thr77Ser in exon 1 of DFNB31: This variant has been reported in one individual w ith Usher syndrome (Aller 2010). However, it is not expected to have clinical si gnificance because the variant has been reported in 0.8% (33/4074) control chrom osomes from a broad, though clinically and racially unspecified population (rs56 204273), and in 1% (77/7014) European and 0.29% (11/3736) African American contr ol chromosomes by the NHBLI Exome Sequencing project (http://evs.gs.washington.e du/EVS). The variant has also been reported in 3/128 (2.3%) Caucasian probands t ested by our laboratory. In addition, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein primarily b ased upon a lack of conservation across species including mammals. Of note, frui tfly has a serine at this position despite high nearby amino acid conservation. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 2D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.015

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.13

Sift

Benign

0.28

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.13

B;P

Vest4

0.081

MutPred

0.44

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.30

MPC

0.79

ClinPred

0.0099

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.39

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