rs1295062471

Variant names:

• chr11-17634837-G-GGGCCAGT
• rs1295062471
• NM_001292063.2:c.7481-5_7482dupGCCAGTG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001292063.2(OTOG):​c.7481-5_7482dupGCCAGTG​(p.Cys2495fs) variant causes a frameshift, splice region 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). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: OTOG NM_001292063.2 frameshift, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7481-5_7482dupGCCAGTG	p.Cys2495fs	frameshift_variant, splice_region_variant	Exon 45 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7517-5_7518dupGCCAGTG	p.Cys2507fs	frameshift_variant, splice_region_variant	Exon 44 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7481-7_7481-6insGGCCAGT		splice_region_variant, intron_variant	Intron 44 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7517-7_7517-6insGGCCAGT		splice_region_variant, intron_variant	Intron 43 of 54	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4606-773_4606-772insGGCCAGT		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 151980 Hom.: 0 Cov.: 32

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: 56 AN: 145702 Hom.: 0 AF XY: 0.000344 AC XY: 27 AN XY: 78520

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.: 0 Cov.: 33 AF XY: 0.000566 AC XY: 390 AN XY: 688786

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: 49 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74362

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.: 0

Bravo AF: 0.000325

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18B Pathogenic:2

Mar 18, 2021

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Nov 17, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1295062471; hg19: chr11-17656384;