rs751127167

Positions:

chr11-17553476-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001292063.2(OTOG):c.499del(p.Val167TrpfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,458,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.08

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-17553476-TG-T is Pathogenic according to our data. Variant chr11-17553476-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.499del	p.Val167TrpfsTer53	frameshift_variant	6/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 linkuse as main transcript	c.535del	p.Val179TrpfsTer53	frameshift_variant	5/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.499del	p.Val167TrpfsTer53	frameshift_variant	6/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.535del	p.Val179TrpfsTer53	frameshift_variant	5/55	5		ENSP00000382323	A2	Q6ZRI0-1
OTOG	ENST00000498332.5 linkuse as main transcript	n.405del		non_coding_transcript_exon_variant	5/16	5
OTOG	ENST00000428619.1 linkuse as main transcript			downstream_gene_variant		3		ENSP00000399057

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000103

AC:

AN:

77876

Hom.:

AF XY:

0.0000764

AC XY:

AN XY:

39242

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1305952

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

634020

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.0000484

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000193

Gnomad4 OTH exome

AF:

0.0000370

GnomAD4 genome

AF:

0.000335

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000355

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Val179Trpfs*53) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs751127167, gnomAD 0.1%). 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: 228284). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2024	Identified with a second OTOG variant in a patient with severe-profound bilateral sensorineural hearing loss in the published literature (PMID: 36515421); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 36147510, 36515421) -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2016

The p.Val179fs variant in OTOG has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/722 of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); h owever, this frequency is low enough to be consistent with a recessive carrier f requency. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 179 and leads to a premature ter mination codon 53 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of Otog in mice resulted in deafness supporting of a los s-of-function mechanism for the disease (Simmler 2000). While these two studies provide evidence of a causative link between loss of function of OTOG and autoso mal recessive hearing loss, to date, no other publications report on OTOG varian ts in individuals with hearing loss. In summary, although additional evidence is required to strengthen the gene-disease association for OTOG and hearing loss, the current data supports a likely pathogenic role for the p.Val179fs variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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