rs34963246

Positions:

• chr9-114404031-G-A
• chr9-114404031-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.750

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
WHRN	NM_015404.4	c.2283C>T	p.Ser761Ser	synonymous_variant	10/12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.2283C>T	p.Ser761Ser	synonymous_variant	10/12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17718 AN: 152186 Hom.: 1256 Cov.: 33

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

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.: 37 AF XY: 0.0864 AC XY: 62761 AN XY: 726752

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.: 33 AF XY: 0.115 AC XY: 8551 AN XY: 74480

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: 94 AN: 3478

EpiCase AF: 0.0803

EpiControl AF: 0.0805

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2009

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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. -

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

Other links and lift over

dbSNP: rs34963246; hg19: chr9-117166311; COSMIC: COSV54335995;