11-17599671-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_001292063.2(OTOG):c.3683C>T(p.Pro1228Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00483 in 1,550,638 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1228T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 17 hom. )

Consequence

OTOG
NM_001292063.2 missense, splice_region

Scores

Splicing: ADA: 0.9945

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:5

Conservation

PhyloP100: 7.05

Publications

6 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: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0033 (502/152324) while in subpopulation NFE AF = 0.00591 (402/68024). AF 95% confidence interval is 0.00543. There are 0 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.3683C>T	p.Pro1228Leu	missense_variant, splice_region_variant	Exon 31 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.3719C>T	p.Pro1240Leu	missense_variant, splice_region_variant	Exon 30 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.3683C>T	p.Pro1228Leu	missense_variant, splice_region_variant	Exon 31 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.3719C>T	p.Pro1240Leu	missense_variant, splice_region_variant	Exon 30 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.1048-2539C>T		intron_variant	Intron 7 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00273

AC:

409

AN:

149550

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.000881

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00196

Gnomad NFE exome

AF:

0.00555

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00500

AC:

6985

AN:

1398314

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

3361

AN XY:

689684

show subpopulations

African (AFR)

AF:

0.000633

AC:

AN:

31596

American (AMR)

AF:

0.00157

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.000199

AC:

AN:

25180

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.000896

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00290

AC:

140

AN:

48226

Middle Eastern (MID)

AF:

0.000702

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00599

AC:

6468

AN:

1078922

Other (OTH)

AF:

0.00379

AC:

220

AN:

58016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

359

718

1077

1436

1795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<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:

0.00330

AC:

502

AN:

152324

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41576

American (AMR)

AF:

0.00183

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68024

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

137

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:

0.00502

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00727

AC:

ExAC

AF:

0.00132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30097855) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BS2 -

Meniere disease

Pathogenic:1Uncertain:1

Jan 01, 2020

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Feb 03, 2025

Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The NM_001292063.2:c.3683C>T is a rare missense variant in the OTOG gene that has been replicated in four patient's across Brazilian and Spanish databases. This variant has an amino acid change at p.P1128L (p.P1240L). This variant may influence splicing processes through the simultaneous creation and elimination of exonic splicing enhancers and silencers, potentially altering exon recognition patterns. In silico analysis using pathogenicity prediction algorithms such as the CADD score (33.00), pLI score (1.23), PolyPhen2 score (1.000) have deemed the variant as "Likely Pathogenic". In silico Protein Stability predictions such as DynaMut2 (-0.49kcal/mol) and MuPro (-0.24kcal/mol) have shown it to destabilize the protein. However, experimental evidence is lacking. This is the first time the variant chr11:17599671C>T have been reported outside Spanish MD patients. For the reasons above and following the ACMG guidelines for variant interpretation, we have classified this variant as "Likely Pathogenic" (PS4, PM2, PP3, PP2, BP1). -

not specified

Benign:1

Jun 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro1240Leu in exon 30 of OTOG: This variant is not expected to have clinical significance because it has been identified in 0.6% (384/67268) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs117005078). Furthermore, this variant has been reported by our la boratory in 10 individuals with hearing loss, including 4 with an alternate gene tic etiology identified. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.076

T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.8

H;.

PhyloP100

7.0

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0020

D;D

Vest4

0.90

MVP

0.80

ClinPred

0.11

GERP RS

5.3

Varity_R

0.29

gMVP

0.84

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.93

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