chr9-114504783-C-G

Position:

chr9-114504783-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015404.4(WHRN):c.19G>C(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,459,668 control chromosomes in the GnomAD database, including 2 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 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 1.22

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004876882).

BP6

Variant 9-114504783-C-G is Benign according to our data. Variant chr9-114504783-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179353.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr9-114504783-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (205/152292) while in subpopulation AFR AF= 0.00399 (166/41576). AF 95% confidence interval is 0.0035. There are 2 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.19G>C	p.Gly7Arg	missense_variant	1/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.19G>C	p.Gly7Arg	missense_variant	1/12	1	NM_015404.4	P1	Q9P202-1
WHRN	ENST00000374057.3 linkuse as main transcript	c.19G>C	p.Gly7Arg	missense_variant	1/2	2			Q9P202-2
WHRN	ENST00000673697.1 linkuse as main transcript	c.19G>C	p.Gly7Arg	missense_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00400

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000509

AC:

AN:

57026

Hom.:

AF XY:

0.000396

AC XY:

AN XY:

32820

show subpopulations

Gnomad AFR exome

AF:

0.00459

Gnomad AMR exome

AF:

0.000547

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000243

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000284

AC:

371

AN:

1307376

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

162

AN XY:

643190

show subpopulations

Gnomad4 AFR exome

AF:

0.00371

Gnomad4 AMR exome

AF:

0.000578

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000745

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.000736

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152292

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00399

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000932

Hom.:

Bravo

AF:

0.00160

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2020	- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 28, 2017

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 09, 2013

Gly7Arg in Exon 1 of DFNB31: This variant is not expected to have clinical signi ficance because the glycine (Gly) residue at position 7 is not conserved in seve ral species with wallaby, opossum, and platypus having an arginine (Arg) at that position. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.66

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

N;N

MutationTaster

Benign

0.75

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.68

N;N

REVEL

Benign

0.034

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.70

T;T

Polyphen

0.12

B;B

Vest4

0.19

MVP

0.27

MPC

1.8

ClinPred

0.067

GERP RS

4.1

Varity_R

0.29

gMVP

0.26

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

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