rs16934404

Positions:

• chr11-17573271-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.2274C>T​(p.Arg758=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,528,074 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (91 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (256 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-17573271-C-T is Benign according to our data. Variant chr11-17573271-C-T is described in ClinVar as [Benign]. Clinvar id is 226867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2274C>T	p.Arg758=	synonymous_variant	19/56	ENST00000399397.6
OTOG	NM_001277269.2	c.2310C>T	p.Arg770=	synonymous_variant	18/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2274C>T	p.Arg758=	synonymous_variant	19/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2310C>T	p.Arg770=	synonymous_variant	18/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3296 AN: 152178 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0176 AC: 2311 AN: 130940 Hom.: 73 AF XY: 0.0163 AC XY: 1162 AN XY: 71224

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0861

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00582 AC: 8009 AN: 1375778 Hom.: 256 Cov.: 32 AF XY: 0.00582 AC XY: 3940 AN XY: 677446

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.0000402

Gnomad4 EAS exome AF: 0.0877

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.0000884

Gnomad4 NFE exome AF: 0.000464

Gnomad4 OTH exome AF: 0.00909

GnomAD4 genome AF: 0.0217 AC: 3302 AN: 152296 Hom.: 91 Cov.: 33 AF XY: 0.0226 AC XY: 1686 AN XY: 74466

Gnomad4 AFR AF: 0.0554

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0884

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0101 Hom.: 14

Bravo AF: 0.0266

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg770Arg in exon 18 of OTOG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 13.0% (26/200) of Ha n Chinese chromosomes from a broad population by the 1000 Genomes Project (http: //www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs16934404). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

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	-0.63
CADD	Benign	0.68
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16934404; hg19: chr11-17594818;