dbSNP rs34963246: WHRN:p.Ser761Ser (chr9-114404031-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015404.4(WHRN):c.2283C>T(p.Ser761Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,613,262 control chromosomes in the GnomAD database, including 8,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1261 hom., cov: 33)

Exomes 𝑓: 0.090 ( 6784 hom. )

Consequence

WHRN
NM_015404.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.750

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 9-114404031-G-A is Benign according to our data. Variant chr9-114404031-G-A is described in ClinVar as [Benign]. Clinvar id is 45669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114404031-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.2283C>T	p.Ser761Ser	synonymous_variant	Exon 10 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.2283C>T	p.Ser761Ser	synonymous_variant	Exon 10 of 12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17718

AN:

152186

Hom.:

1256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0907

Gnomad OTH

AF:

0.0889

GnomAD3 exomes

AF:

0.0914

AC:

22906

AN:

250592

Hom.:

1391

AF XY:

0.0843

AC XY:

11423

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0253

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.0928

Gnomad OTH exome

AF:

0.0813

GnomAD4 exome

AF:

0.0901

AC:

131660

AN:

1460958

Hom.:

6784

Cov.:

AF XY:

0.0864

AC XY:

62761

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.202

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.0359

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0254

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.0932

Gnomad4 OTH exome

AF:

0.0851

GnomAD4 genome

AF:

0.116

AC:

17738

AN:

152304

Hom.:

1261

Cov.:

AF XY:

0.115

AC XY:

8551

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.0346

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.0245

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0908

Gnomad4 OTH

AF:

0.0880

Alfa

AF:

0.0983

Hom.:

422

Bravo

AF:

0.123

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0803

EpiControl

AF:

0.0805

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Usher syndrome type 2D

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

3.7

DANN

Benign

0.73

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