rs942519

Positions:

• chr9-114406753-A-G
• chr9-114406753-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.1838T>C​(p.Met613Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,613,758 control chromosomes in the GnomAD database, including 234,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18272 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215755 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.9923813E-6).
• BP6: Variant 9-114406753-A-G is Benign according to our data. Variant chr9-114406753-A-G is described in ClinVar as [Benign]. Clinvar id is 45663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114406753-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1838T>C	p.Met613Thr	missense_variant	9/12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1838T>C	p.Met613Thr	missense_variant	9/12	1	NM_015404.4	ENSP00000354623	P1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73752 AN: 151974 Hom.: 18256 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.500

GnomAD3 exomes AF: 0.529 AC: 132256 AN: 249862 Hom.: 35326 AF XY: 0.536 AC XY: 72453 AN XY: 135258

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.607

Gnomad EAS exome AF: 0.499

Gnomad SAS exome AF: 0.593

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.542 AC: 791630 AN: 1461664 Hom.: 215755 Cov.: 99 AF XY: 0.544 AC XY: 395471 AN XY: 727110

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.536

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.545

Gnomad4 OTH exome AF: 0.533

GnomAD4 genome AF: 0.485 AC: 73800 AN: 152094 Hom.: 18272 Cov.: 32 AF XY: 0.482 AC XY: 35876 AN XY: 74356

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.505

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.495

Alfa AF: 0.533 Hom.: 41288

Bravo AF: 0.482

TwinsUK AF: 0.546 AC: 2023

ALSPAC AF: 0.559 AC: 2156

ESP6500AA AF: 0.387 AC: 1703

ESP6500EA AF: 0.546 AC: 4695

ExAC AF: 0.529 AC: 64172

Asia WGS AF: 0.479 AC: 1667 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.546

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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 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 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 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
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.18
DEOGEN2	Benign	0.047	.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.019	T;T;T
MetaRNN	Benign	0.0000070	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	.;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.45	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.014
MPC		0.14
ClinPred		0.0037	T
GERP RS		0.056
Varity_R		0.042
gMVP		0.17

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: rs942519; hg19: chr9-117169033; COSMIC: COSV54327986;