rs2274159

chr9-114403966-A-Gchr9-114403966-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.2348T>C(p.Val783Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,610,410 control chromosomes in the GnomAD database, including 191,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V783E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.41 (14062 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177104 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.944

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=4.0899216E-5).
• BP6: Variant 9-114403966-A-G is Benign according to our data. Variant chr9-114403966-A-G is described in ClinVar as [Benign]. Clinvar id is 45672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114403966-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.2348T>C	p.Val783Ala	missense_variant	10/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.2348T>C	p.Val783Ala	missense_variant	10/12	1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62811 AN: 151658 Hom.: 14055 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.481 AC: 120111 AN: 249582 Hom.: 29689 AF XY: 0.489 AC XY: 65998 AN XY: 135002

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.490 AC: 714533 AN: 1458632 Hom.: 177104 Cov.: 74 AF XY: 0.493 AC XY: 357504 AN XY: 725716

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.491

Gnomad4 ASJ exome AF: 0.596

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.540

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.414 AC: 62835 AN: 151778 Hom.: 14062 Cov.: 32 AF XY: 0.413 AC XY: 30639 AN XY: 74164

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.518

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.444

Alfa AF: 0.481 Hom.: 38917

Bravo AF: 0.406

TwinsUK AF: 0.489 AC: 1814

ALSPAC AF: 0.506 AC: 1950

ESP6500AA AF: 0.237 AC: 1043

ESP6500EA AF: 0.500 AC: 4299

ExAC AF: 0.479 AC: 58101

Asia WGS AF: 0.414 AC: 1440 AN: 3478

EpiCase AF: 0.496

EpiControl AF: 0.502

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29083408) -

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 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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.50
Dann	Benign	0.39
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.12	T;T;T
MetaRNN	Benign	0.000041	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.72	N;N;N
REVEL	Benign	0.032
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.020
MPC		0.15
ClinPred		0.00058	T
GERP RS		1.1
Varity_R		0.019
gMVP		0.13

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: rs2274159; hg19: chr9-117166246; COSMIC: COSV54328267;