rs56204273

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T77T) has been classified as Likely benign.

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

Publications

7 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 -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 VariationId is 45671.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.229A>T	p.Thr77Ser	missense_variant	Exon 1 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.229A>T	p.Thr77Ser	missense_variant	Exon 1 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

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

GnomAD2 exomes

AF:

0.00742

AC:

1789

AN:

241140

AF XY:

0.00823

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 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

African (AFR)

AF:

0.00161

AC:

AN:

33466

American (AMR)

AF:

0.00351

AC:

157

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00724

AC:

189

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0135

AC:

1168

AN:

86236

European-Finnish (FIN)

AF:

0.00158

AC:

AN:

51132

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0107

AC:

11852

AN:

1111714

Other (OTH)

AF:

0.00944

AC:

570

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1030

2060

3091

4121

5151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.00652

AC:

993

AN:

152368

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

479

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41584

American (AMR)

AF:

0.00712

AC:

109

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0164

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00976

AC:

664

AN:

68042

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00664

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

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WHRN: BS1, BS2 -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 15, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.7

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

Mutation Taster

=92/8

polymorphism

(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