chr11-17574890-C-T

Position:

chr11-17574890-C-T

Variant summary

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

The NM_001292063.2(OTOG):c.2464C>T(p.Gln822*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,526,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.54

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 11-17574890-C-T is Pathogenic according to our data. Variant chr11-17574890-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17574890-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2464C>T	p.Gln822*	stop_gained	20/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.2500C>T	p.Gln834*	stop_gained	19/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.2464C>T	p.Gln822*	stop_gained	20/56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 link	c.2500C>T	p.Gln834*	stop_gained	19/55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000384

AC:

AN:

127718

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

67734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000435

Gnomad ASJ exome

AF:

0.00126

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000268

Gnomad NFE exome

AF:

0.000772

Gnomad OTH exome

AF:

0.000271

GnomAD4 exome

AF:

0.000410

AC:

563

AN:

1374426

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

299

AN XY:

674970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000584

Gnomad4 ASJ exome

AF:

0.00166

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000191

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.000351

GnomAD4 genome

AF:

0.000361

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000722

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000376

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 18B

Pathogenic:5

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 26, 2022	This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PM3_STR -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2024	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 22, 2021	ACMG codes:PVS1, PM2, PP5 -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change creates a premature translational stop signal (p.Gln834*) 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 (rs554847663, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 29907799). ClinVar contains an entry for this variant (Variation ID: 417941). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2024	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; This variant is associated with the following publications: (PMID: 10655058, 29907799, 32860223, 33105617, 34426522, 36147510, 34515852) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	OTOG: PVS1, PM2 -

Seizure;C3714756:Intellectual disability

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Feb 07, 2019

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2020

The p.Gln834X variant in OTOG has been identified in 4 individuals with hearing loss: 2 heterozygotes where a second variant was not identified on the other copy of OTOG, in 1 homozygote, and in 1 compound heterozygote with a second pathogenic OTOG variant (Sheppard 2018 PMID: 29907799, LMM data). Both variants segregated with hearing loss in an affected sibling (LMM data). The p.Gln834X variant has also been reported by other clinical laboratories in ClinVar (Variation ID 417941) and has been identified in 0.12% (8/6636) of Ashkenazi Jewish and in 0.08% (51/60760) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 834, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOG gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3, PP1, BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

Vest4

0.31

GERP RS

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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