rs34252199

Variant names:

• chr9-114423425-C-T
• rs34252199
• NM_015404.4:c.1515G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015404.4(WHRN):​c.1515G>A​(p.Ala505Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,614,046 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (89 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1616 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.31

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-114423425-C-T is Benign according to our data. Variant chr9-114423425-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114423425-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.31 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1515G>A	p.Ala505Ala	synonymous_variant	Exon 7 of 12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1515G>A	p.Ala505Ala	synonymous_variant	Exon 7 of 12	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4698 AN: 152052 Hom.: 89 Cov.: 31

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0306 AC: 7700 AN: 251446 Hom.: 165 AF XY: 0.0312 AC XY: 4237 AN XY: 135894

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0451 AC: 65939 AN: 1461876 Hom.: 1616 Cov.: 32 AF XY: 0.0445 AC XY: 32343 AN XY: 727238

Gnomad4 AFR exome AF: 0.00803

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00589

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.0150

Gnomad4 NFE exome AF: 0.0528

Gnomad4 OTH exome AF: 0.0391

GnomAD4 genome AF: 0.0309 AC: 4696 AN: 152170 Hom.: 89 Cov.: 31 AF XY: 0.0295 AC XY: 2197 AN XY: 74396

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0326

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0490

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0394 Hom.: 54

Bravo AF: 0.0304

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0442

EpiControl AF: 0.0443

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 12, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Usher syndrome type 2D Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.48
DANN	Benign	0.67

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: rs34252199; hg19: chr9-117185705;