rs185432248

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001292063.2(OTOG):c.5252G>A(p.Arg1751His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,549,836 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -2.58

Publications

2 publications found

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005325198).

BP6

Variant 11-17610552-G-A is Benign according to our data. Variant chr11-17610552-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227784.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00119 (180/151682) while in subpopulation NFE AF = 0.00187 (127/67862). AF 95% confidence interval is 0.00161. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.5252G>A	p.Arg1751His	missense_variant	Exon 36 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.5288G>A	p.Arg1763His	missense_variant	Exon 35 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.5252G>A	p.Arg1751His	missense_variant	Exon 36 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.5288G>A	p.Arg1763His	missense_variant	Exon 35 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.2590G>A		non_coding_transcript_exon_variant	Exon 12 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

180

AN:

151562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000854

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.00113

AC:

168

AN:

148532

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.000294

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.000371

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00177

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00205

AC:

2860

AN:

1398154

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1384

AN XY:

689568

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

31596

American (AMR)

AF:

0.000925

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.000278

AC:

AN:

25156

East Asian (EAS)

AF:

0.000112

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.00166

AC:

AN:

48216

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00243

AC:

2627

AN:

1078888

Other (OTH)

AF:

0.00160

AC:

AN:

57992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

198

397

595

794

992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00119

AC:

180

AN:

151682

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74096

show subpopulations

African (AFR)

AF:

0.000484

AC:

AN:

41364

American (AMR)

AF:

0.000853

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.000777

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

67862

Other (OTH)

AF:

0.00143

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000854

Hom.:

Bravo

AF:

0.00122

ExAC

AF:

0.000507

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1763 of the OTOG protein (p.Arg1763His). This variant is present in population databases (rs185432248, gnomAD 0.2%), 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 OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 227784). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

May 20, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BP4 -

not specified

Benign:1

Jul 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg1763His in exon 35 of OTOG: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, >20 mammals have a Histidine (His) at this position despite high nearby a mino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. It has been identified in 0.16% ( 105/66772) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs185432248). -

OTOG-related disorder

Benign:1

Aug 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0010

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.

PhyloP100

-2.6

PrimateAI

Benign

0.21

PROVEAN

Benign

0.45

N;.

REVEL

Benign

0.027

Sift

Benign

0.89

T;.

Sift4G

Benign

0.42

T;T

Vest4

0.018

MVP

0.014

ClinPred

0.0038

GERP RS

-12

Varity_R

0.015

gMVP

0.27

Mutation Taster

=98/2

polymorphism

(source)

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

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rs185432248

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over