rs876657656

Variant summary

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

The NM_001292063.2(OTOG):c.2453_2454insACTGGACACCCA(p.Tyr818delinsTer) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000111 in 1,537,294 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 stop_gained

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.58

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 11-17574878-T-TAACTGGACACCC is Pathogenic according to our data. Variant chr11-17574878-T-TAACTGGACACCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.2453_2454insACTGGACACCCA	p.Tyr818delinsTer	stop_gained	20/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.2489_2490insACTGGACACCCA	p.Tyr830delinsTer	stop_gained	19/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.2453_2454insACTGGACACCCA	p.Tyr818delinsTer	stop_gained	20/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.2489_2490insACTGGACACCCA	p.Tyr830delinsTer	stop_gained	19/55	5		A2	Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

GnomAD3 exomes

AF:

0.0000810

AC:

AN:

135794

Hom.:

AF XY:

0.0000552

AC XY:

AN XY:

72480

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000425

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:

0.000256

GnomAD4 exome

AF:

0.0000108

AC:

AN:

1385094

Hom.:

Cov.:

AF XY:

0.00000733

AC XY:

AN XY:

681774

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000431

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228283). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.05%). This sequence change creates a premature translational stop signal (p.Tyr830*) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2023	Nonsense 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; Has not been previously published as pathogenic or benign to our knowledge -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2016

The p.Tyr830X variant in OTOG has been previously reported by our laboratory in the homozygous state in one individual with mild to moderate hearing loss. This variant has not been identified in large population studies, though the ability of these studies to accurately detect insertions or deletions may be limited. T his variant creates a premature termination codon at position 830, which is pred icted to lead 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 (Schraders 2012), and disruption of Otog in mice resulted in deafness supportin g of a loss-of-function mechanism for the disease (Simmler 2000). In summary, al though additional evidence is required to strengthen the gene-disease associatio n for OTOG and hearing loss, the p.Tyr830 variant is likely pathogenic based on its predicted impact on the protein and our currently knowledge of the gene. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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