rs45527543

Positions:

• chr9-114504769-G-C

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.33C>G​(p.Ser11Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00155 in 1,495,928 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 3.63

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=0.0064022243).
• BP6: Variant 9-114504769-G-C is Benign according to our data. Variant chr9-114504769-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45677.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=5}. Variant chr9-114504769-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00129 (197/152296) while in subpopulation NFE AF= 0.00199 (135/68006). AF 95% confidence interval is 0.00171. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WHRN	NM_015404.4	c.33C>G	p.Ser11Arg	missense_variant	1/12	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.33C>G	p.Ser11Arg	missense_variant	1/12	1	NM_015404.4	ENSP00000354623	P1
WHRN	ENST00000374057.3	c.33C>G	p.Ser11Arg	missense_variant	1/2	2		ENSP00000363170
WHRN	ENST00000673697.1	c.33C>G	p.Ser11Arg	missense_variant	2/2			ENSP00000501152

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152188 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00111 AC: 101 AN: 90864 Hom.: 0 AF XY: 0.00107 AC XY: 55 AN XY: 51210

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000395

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.00158 AC: 2123 AN: 1343632 Hom.: 4 Cov.: 34 AF XY: 0.00150 AC XY: 994 AN XY: 662574

Gnomad4 AFR exome AF: 0.000291

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152296 Hom.: 0 Cov.: 34 AF XY: 0.00128 AC XY: 95 AN XY: 74478

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00158

ExAC AF: 0.000415 AC: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2022	The p.Ser11Arg variant (rs45527543) has been previously reported in a patient with a clinical diagnosis of Usher Syndrome II (Bonnet 2011). However, the patient reported in Bonnet et al (2011) carried no other relevant variants in the WHRN gene, but did harbor two pathogenic variants in ADGRV1 in a trans heterozygous configuration. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.37% (identified in 21 out of 5,650 chromosomes), and is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 45677). The serine at codon 11 is moderately conserved considering 12 species (Alamut software v2.9), and computational analyses suggest this variant has/does not have a significant effect on WHRN protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Ser11Arg variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2022	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2015

p.Ser11Arg in exon 1 of DFNB31 variant is not expected to have clinical signific ance because it has been identified in 0.5% (10/1860) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s45527543). In addition, computational prediction tools and conservation data su ggest the variant may not impact the protein. -

Retinitis pigmentosa-deafness syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.056
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.89	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.0	B;B
Vest4		0.22
MutPred		0.20		Loss of phosphorylation at S11 (P = 0.0172);Loss of phosphorylation at S11 (P = 0.0172);
MVP		0.30
MPC		1.7
ClinPred		0.10	T
GERP RS		5.0
Varity_R		0.25
gMVP		0.49

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: rs45527543; hg19: chr9-117267049;