rs61743165

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292063.2(OTOG):c.7400G>A(p.Arg2467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,550,382 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 118 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1248 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.11

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020101964).

BP6

Variant 11-17634201-G-A is Benign according to our data. Variant chr11-17634201-G-A is described in ClinVar as [Benign]. Clinvar id is 226908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.7400G>A	p.Arg2467His	missense_variant	Exon 44 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.7436G>A	p.Arg2479His	missense_variant	Exon 43 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.7400G>A	p.Arg2467His	missense_variant	Exon 44 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.7436G>A	p.Arg2479His	missense_variant	Exon 43 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.4605+327G>A		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5627

AN:

152108

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0517

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0345

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0405

AC:

5947

AN:

146874

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0432

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00195

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0386

AC:

54026

AN:

1398156

Hom.:

1248

Cov.:

AF XY:

0.0399

AC XY:

27491

AN XY:

689606

show subpopulations

African (AFR)

AF:

0.0367

AC:

1158

AN:

31594

American (AMR)

AF:

0.0418

AC:

1494

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

638

AN:

25182

East Asian (EAS)

AF:

0.00151

AC:

AN:

35738

South Asian (SAS)

AF:

0.0846

AC:

6705

AN:

79226

European-Finnish (FIN)

AF:

0.0313

AC:

1505

AN:

48132

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0375

AC:

40458

AN:

1078946

Other (OTH)

AF:

0.0337

AC:

1951

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3319

6637

9956

13274

16593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0370

AC:

5636

AN:

152226

Hom.:

118

Cov.:

AF XY:

0.0388

AC XY:

2887

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0375

AC:

1559

AN:

41544

American (AMR)

AF:

0.0519

AC:

794

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5172

South Asian (SAS)

AF:

0.0878

AC:

423

AN:

4820

European-Finnish (FIN)

AF:

0.0345

AC:

366

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0341

AC:

2321

AN:

67984

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

284

568

852

1136

1420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0342

Hom.:

129

Bravo

AF:

0.0347

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0374

AC:

144

ExAC

AF:

0.0445

AC:

927

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg2479His in exon 43 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 4.5% (6/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs61743165). -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

OTOG-related disorder

Benign:1

Mar 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.076

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.080

N;.

REVEL

Benign

0.059

Sift

Benign

0.22

T;.

Sift4G

Benign

0.67

T;T

Vest4

0.028

ClinPred

0.0037

GERP RS

2.8

Varity_R

0.041

gMVP

0.39

Mutation Taster

=96/4

polymorphism (auto)

(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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rs61743165

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