9-114478722-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015404.4(WHRN):c.668G>A(p.Arg223His) variant causes a missense change. The variant allele was found at a frequency of 0.00338 in 1,612,430 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (61 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.67

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008132726).
• BP6: Variant 9-114478722-C-T is Benign according to our data. Variant chr9-114478722-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45681.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr9-114478722-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00237 (361/152266) while in subpopulation SAS AF= 0.0323 (156/4826). AF 95% confidence interval is 0.0282. There are 5 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.668G>A	p.Arg223His	missense_variant	2/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.668G>A	p.Arg223His	missense_variant	2/12	1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152148 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00628 AC: 1559 AN: 248324 Hom.: 28 AF XY: 0.00750 AC XY: 1009 AN XY: 134504

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0246

Gnomad SAS exome AF: 0.0316

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000940

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00349 AC: 5096 AN: 1460164 Hom.: 61 Cov.: 31 AF XY: 0.00430 AC XY: 3122 AN XY: 726380

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0160

Gnomad4 SAS exome AF: 0.0302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152266 Hom.: 5 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74446

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00172 Hom.: 4

Bravo AF: 0.00186

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00628 AC: 763

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000653

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2015	Arg223His in exon 2 of DFNB31: This variant is not expected to have clinical sig nificance because it has been identified in 3.3% (511/15606) of South Asian chro mosomes including 10 homozygotes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs146273185). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -

Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 2D Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.17
Sift	Benign	0.050	D;T
Sift4G	Uncertain	0.024	D;D
Polyphen		0.99	D;D
Vest4		0.39
MVP		0.55
MPC		1.5
ClinPred		0.052	T
GERP RS		5.5
Varity_R		0.33
gMVP		0.43

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: rs146273185; hg19: chr9-117241002; COSMIC: COSV54331076;