rs149897775

Positions:

chr9-114403897-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_015404.4(WHRN):c.2417C>T(p.Pro806Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000758 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P806Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

WHRN
NM_015404.4 missense, splice_region

Scores

Splicing: ADA: 0.6713

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.60

Variant links:

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]

WHRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036877632).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000361 (55/152254) while in subpopulation AFR AF= 0.00123 (51/41548). AF 95% confidence interval is 0.000958. There are 0 homozygotes in gnomad4. There are 24 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	Protein	UniProt
WHRN	NM_015404.4 link	c.2417C>T	p.Pro806Leu	missense_variant, splice_region_variant	10/12	ENST00000362057.4	NP_056219.3	Q9P202-1B9EGE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 link	c.2417C>T	p.Pro806Leu	missense_variant, splice_region_variant	10/12	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000964

AC:

AN:

248840

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

134714

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000459

AC:

AN:

1458246

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

725584

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000361

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000721

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2024	Variant summary: WHRN c.2417C>T (p.Pro806Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 248840 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in WHRN causing Usher Syndrome (9.6e-05 vs 0.0038), allowing no conclusion about variant significance. c.2417C>T has been reported in the literature in an individual affected with non-syndromic hearing loss (Sloan-Heggen_2016). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 228562). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2015	The p.Pro806Leu variant in DFNB31 has not been previously reported in individual s with hearing loss, but has been identified in 0.16% (17/10380) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs149897775). Computational prediction tools and conservation analyses suggest that the p.Pro806Leu variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of this variant is uncertain. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	Observed in published literature in a patient with hearing loss, described as c.1268 C>T, p.P423L using alternate nomenclature (Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26969326) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 806 of the WHRN protein (p.Pro806Leu). This variant is present in population databases (rs149897775, gnomAD 0.1%). This missense change has been observed in individual(s) with early-onset hearing loss (PMID: 26969326). This variant is also known as c.1268C>T (p.Pro423Leu). ClinVar contains an entry for this variant (Variation ID: 228562). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;.;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

N;N;D

REVEL

Benign

0.16

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.99, 0.98

.;D;D

Vest4

0.54

MVP

0.50

MPC

0.49

ClinPred

0.17

GERP RS

5.0

Varity_R

0.24

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.67

dbscSNV1_RF

Benign

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over