9-114426229-G-T

Variant names:

• chr9-114426229-G-T
• rs147283064
• NM_015404.4:c.1148C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_015404.4(WHRN):​c.1148C>A​(p.Thr383Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,612,392 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T383T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (3 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.532
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015101612).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000519 (79/152292) while in subpopulation NFE AF = 0.00107 (73/68014). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.1148C>A	p.Thr383Asn	missense	Exon 4 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.1148C>A	p.Thr383Asn	missense	Exon 4 of 12	NP_001166896.1
	WHRN	NM_001083885.3		c.-2C>A		5_prime_UTR	Exon 4 of 12	NP_001077354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1148C>A	p.Thr383Asn	missense	Exon 4 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.-2C>A		5_prime_UTR	Exon 4 of 12	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.1148C>A	p.Thr383Asn	missense	Exon 4 of 11	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251198 AF XY: 0.000273

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000760 AC: 1109 AN: 1460100 Hom.: 3 Cov.: 30 AF XY: 0.000727 AC XY: 528 AN XY: 726358

African (AFR) AF: 0.0000898 AC: 3 AN: 33422

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4346

European-Non Finnish (NFE) AF: 0.000960 AC: 1067 AN: 1112000

Other (OTH) AF: 0.000498 AC: 30 AN: 60236

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74470

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Sep 17, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in patients with hearing loss or Usher syndrome in published literature; however, these patients either harbored variants in other genes or had no specific information provided (PMID: 23804846, 20352026); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135276, 20352026, 30245029, 23804846, 34753855)

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 383 of the WHRN protein (p.Thr383Asn). This variant is present in population databases (rs147283064, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 163051). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not specified Uncertain:1

Mar 26, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Thr383Asn var iant in DFNB31 has been reported in four individuals with hearing loss and retin itis pigmentosa (Aller 2010; LOVD, https://grenada.lumc.nl/LOVD2/Usher_montpell ier & Le Quesne Stabej 2012; LMM data) and two individuals with hearing loss (Sh earer 2013 and LMM data). However, a second DFNB31 variant was not identified in any of the six individuals, and two individuals harbored pathogenic variants in different genes that were sufficient to explain the patient's clinical features (Shearer 2013; LOVD, https://grenada.lumc.nl/LOVD2/Usher_montpellier & Le Quesn e Stabej 2012). This variant has been identified in 73/126514 European Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147283064 ); however this frequency is not high enough to rule out a pathogenic role. Thre onine (Thr) at position 383 is not conserved in mammals or evolutionarily distan t species, and 2 mammals (Chinese hamster and golden hamster) carry an asparagin e (Asn), supporting that this change may be tolerated. Additional computational prediction tools are limited or unavailable for this variant. In summary, while the clinical significance of the p.Thr383Asn variant is uncertain, the absence o f a second DFNB31 variant in affected individuals carrying this variant, its pre sence in the general population, and the conservation data supporting an unlikel y impact to the protein, suggest that it is more likely to be benign.

Hearing impairment Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Moderate, BP4_Supporting

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 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Usher syndrome type 2D;C1846839:Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1

Aug 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.8
DANN	Benign	0.85
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.53
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.028
Sift	Benign	0.093	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.038
MVP		0.088
MPC		0.14
ClinPred		0.015	T
GERP RS		3.2
Varity_R		0.023
gMVP		0.34
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147283064; hg19: chr9-117188509;