chr11-17609906-C-T

Position:

chr11-17609906-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001292063.2(OTOG):c.4606C>T(p.Leu1536Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,521,602 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 87 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.469

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 links:

OTOG (HGNC:):

OTOG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030214787).

BP6

Variant 11-17609906-C-T is Benign according to our data. Variant chr11-17609906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.4606C>T	p.Leu1536Phe	missense_variant	36/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.4642C>T	p.Leu1548Phe	missense_variant	35/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.4606C>T	p.Leu1536Phe	missense_variant	36/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.4642C>T	p.Leu1548Phe	missense_variant	35/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.1944C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes

AF:

0.00800

AC:

1215

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00201

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00823

AC:

1023

AN:

124278

Hom.:

AF XY:

0.00822

AC XY:

535

AN XY:

65124

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00825

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.00318

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0110

AC:

15009

AN:

1369522

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

7365

AN XY:

671574

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.00913

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.0000282

Gnomad4 SAS exome

AF:

0.00263

Gnomad4 FIN exome

AF:

0.00316

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00967

GnomAD4 genome

AF:

0.00798

AC:

1213

AN:

152080

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

574

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00198

Gnomad4 AMR

AF:

0.0126

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00907

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0112

AC:

ExAC

AF:

0.00389

AC:

112

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	OTOG: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Leu1548Phe in exon 35 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 4.2% (5/120) of Colombian chromosome s from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.g ov/projects/SNP; dbSNP rs117380920). -

Meniere disease

Benign:1

Likely benign, criteria provided, single submitter

case-control

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)

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.98

N;.

REVEL

Benign

0.040

Sift

Uncertain

0.015

D;.

Sift4G

Uncertain

0.056

T;D

Vest4

0.045

MVP

0.095

ClinPred

0.0042

GERP RS

2.4

Varity_R

0.068

gMVP

0.28

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