rs1295062471

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):c.7481-5_7482dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,548,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:1

Conservation

PhyloP100: 1.07

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.7481-5_7482dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.7517-5_7518dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.7481-5_7482dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.7517-5_7518dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5		A2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.4606-771_4606-765dup	intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000384

AC:

AN:

145702

Hom.:

AF XY:

0.000344

AC XY:

AN XY:

78520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

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:

0.000972

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.000563

AC:

786

AN:

1396630

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

390

AN XY:

688786

show subpopulations

Gnomad4 AFR exome

AF:

0.0000634

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000104

Gnomad4 NFE exome

AF:

0.000702

Gnomad4 OTH exome

AF:

0.000311

GnomAD4 genome

AF:

0.000322

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000325

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2022	Identified with a second OTOG variant, phase unknown, in a patient with moderate sporadic hearing loss in the published literature (Safka Brozkova et al., 2020); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32860223) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	- -

Autosomal recessive nonsyndromic hearing loss 18B

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Mar 18, 2021	OTOG c.7517-5_7518dup is predicted to introduce a cryptic splice acceptor within the sequence of the in-tandem duplication in OTOG intron 43. The cryptic splice acceptor in OTOG intron 43 occurs upstream of the OTOG exon 44 canonical splice and is predicted to result in inclusion of the mutant exon with the 7bp duplication leading to a premature stop. Consequence of this in-tandem duplication would be splicing of OTOG exon 44 occurring at the cryptic splice acceptor and resulting in a 7bp insertion in the OTOG message and premature stop at codon 2510 of 2926. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2015

The c.7517-5_7518dup variant in OTOG has been previously reported in one individ ual with hearing loss; however, a variant affecting the remaining copy of OTOG w as not detected in this individual and an alternate genetic explanation for thei r disease was identified(LMM unpublished data). Data from large population studi es is insufficient to assess the frequency of this variant. This variant is a ta ndem duplication of 7 base pairs that encompass the 3' splice junction of intron 43 in the OTOG gene. However, it is not clear whether this will result in splic ing to occur at a novel 3' splice site downstream of the nascent splice site, wh ich would not impact the protein, or if splicing occurs at the nascent splice si te, which would result in a frameshift of the coding sequence and therefore, be deleterious to the protein. Computational tools predict that splicing would occu r at the novel 3' splice site and thus would not result in a frameshift of the c oding sequence; however, functional studies are needed to determine which of the se scenarios is correct. In summary, the clinical significance of the c.7517-5_7 518dup variant is uncertain. -

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