rs141010212

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.2398G>A(p.Asp800Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,550,332 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D800H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.515

Publications

0 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=0.00420323).

BP6

Variant 11-17574824-G-A is Benign according to our data. Variant chr11-17574824-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00265 (403/152356) while in subpopulation AFR AF = 0.00921 (383/41588). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2398G>A	p.Asp800Asn	missense_variant	Exon 20 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.2434G>A	p.Asp812Asn	missense_variant	Exon 19 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.2398G>A	p.Asp800Asn	missense_variant	Exon 20 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.2434G>A	p.Asp812Asn	missense_variant	Exon 19 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

404

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00926

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000572

AC:

AN:

148710

AF XY:

0.000401

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.0000816

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000242

AC:

338

AN:

1397976

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

145

AN XY:

689466

show subpopulations

African (AFR)

AF:

0.00908

AC:

287

AN:

31594

American (AMR)

AF:

0.000196

AC:

AN:

35642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.000140

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48216

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

1078820

Other (OTH)

AF:

0.000379

AC:

AN:

57994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

152356

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00921

AC:

383

AN:

41588

American (AMR)

AF:

0.000784

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00355

Hom.:

Bravo

AF:

0.00309

ExAC

AF:

0.000417

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BP4 -

Nov 02, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp812Asn in exon 19 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (184/17160) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs141010212). -

Jul 25, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

OTOG-related disorder

Benign:1

Mar 18, 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

0.078

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.8

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.056

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.

PhyloP100

-0.52

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.090

N;.

REVEL

Benign

0.019

Sift

Benign

0.22

T;.

Sift4G

Benign

0.98

T;T

Vest4

0.061

MVP

0.040

ClinPred

0.0042

GERP RS

-3.8

Varity_R

0.026

gMVP

0.46

Mutation Taster

=94/6

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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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