rs55749855

chr9-114403248-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_015404.4(WHRN):c.2510G>A(p.Arg837His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000831 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R837C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.29

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25473064).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000552 (84/152308) while in subpopulation NFE AF= 0.001 (68/68014). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.2510G>A	p.Arg837His	missense_variant	11/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.2510G>A	p.Arg837His	missense_variant	11/12	1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000773 AC: 194 AN: 251086 Hom.: 0 AF XY: 0.000795 AC XY: 108 AN XY: 135810

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000861 AC: 1258 AN: 1461840 Hom.: 1 Cov.: 31 AF XY: 0.000888 AC XY: 646 AN XY: 727222

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000954

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74462

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000740 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 837 of the WHRN protein (p.Arg837His). This variant is present in population databases (rs55749855, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 228563). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 05, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Arg837His variant in WHRN has been previously identified by our laboratory in 4 individuals with hearing loss; however, a second WHRN variant was not detected in any of these individuals. This variant has also been identified in 0.12% (151/128928) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;D;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.68
MVP		0.63
MPC		0.64
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.78
gMVP		0.44

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: rs55749855; hg19: chr9-117165528;