rs182750732

chr11-17645736-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.8542-8C>T 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 0.00865 in 1,550,846 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (78 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004959
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.61

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-17645736-C-T is Benign according to our data. Variant chr11-17645736-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8542-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.8578-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8542-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8578-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 838 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00967

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00463 AC: 695 AN: 150154 Hom.: 6 AF XY: 0.00487 AC XY: 393 AN XY: 80684

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000577

Gnomad FIN exome AF: 0.000651

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00899 AC: 12571 AN: 1398484 Hom.: 78 Cov.: 32 AF XY: 0.00868 AC XY: 5988 AN XY: 689750

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000745

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74508

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00967

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00759 Hom.: 3

Bravo AF: 0.00550

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOG: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2015	c.8578-8C>T in intron 54 of OTOG: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the spl ice consensus sequence and is therefore unlikely to impact splicing. It has been identified in 0.5% (27/5570) of European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs182750732). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	2.1
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs182750732; hg19: chr11-17667283;