11-17553211-G-A

Position:

chr11-17553211-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001292063.2(OTOG):c.385G>A(p.Val129Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,550,382 control chromosomes in the GnomAD database, including 3 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).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 3 hom. )

Consequence

OTOG
NM_001292063.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1

Conservation

PhyloP100: 9.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.385G>A	p.Val129Met	missense_variant, splice_region_variant	5/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.421G>A	p.Val141Met	missense_variant, splice_region_variant	4/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.385G>A	p.Val129Met	missense_variant, splice_region_variant	5/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.421G>A	p.Val141Met	missense_variant, splice_region_variant	4/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000428619.1 link	c.202G>A	p.Val68Met	missense_variant, splice_region_variant	3/4	3		ENSP00000399057.2	C9IZ84
OTOG	ENST00000498332.5 link	n.291G>A		splice_region_variant, non_coding_transcript_exon_variant	4/16	5

Frequencies

GnomAD3 genomes

AF:

0.000835

AC:

127

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000880

AC:

130

AN:

147698

Hom.:

AF XY:

0.000892

AC XY:

AN XY:

79616

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000888

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000914

AC:

1278

AN:

1398080

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

620

AN XY:

689586

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.0000795

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000126

Gnomad4 FIN exome

AF:

0.0000416

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000931

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152302

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000824

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000282

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 21, 2023	The p.Val141Met variant in OTOG has been previously reported in 1 individual with hearing loss, but a variant affecting the remaining copy of OTOG was not identified (LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 229094) and has been identified in 1.3% (4/316) of Middle Eastern and 0.17% (27/15286) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the last base of the exon, which is part of the 5’ splice region. Splice site computational tools suggest a possible impact to splicing, however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val141Met variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	OTOG: PP3, BS1:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the OTOG protein (p.Val141Met). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs552304627, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. 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: 229094). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Meniere disease

Pathogenic:1

Likely pathogenic, flagged submission

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

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 16, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

OTOG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The OTOG c.421G>A variant is predicted to result in the amino acid substitution p.Val141Met. This variant was reported in an individual with non-syndromic hearing loss (Table S6, Quaio et al. 2022. PubMed ID: 36147510). This variant is reported in 0.19% of alleles in individuals of Latino descent in gnomAD, including one homozygous individual. While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.030

T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.3

N;.;.

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.50

MVP

0.29

ClinPred

0.084

GERP RS

5.4

Varity_R

0.31

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.15

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