rs61731248

chr11-17559106-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):c.1158G>A(p.Ala386=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,545,220 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (271 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (456 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.58

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-17559106-G-A is Benign according to our data. Variant chr11-17559106-G-A is described in ClinVar as [Benign]. Clinvar id is 226861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1158G>A	p.Ala386=	synonymous_variant	11/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1194G>A	p.Ala398=	synonymous_variant	10/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1158G>A	p.Ala386=	synonymous_variant	11/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1194G>A	p.Ala398=	synonymous_variant	10/55	5		A2
OTOG	ENST00000498332.5	n.1064G>A		non_coding_transcript_exon_variant	10/16	5

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5515 AN: 152162 Hom.: 271 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0955

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0203 AC: 2901 AN: 142584 Hom.: 111 AF XY: 0.0174 AC XY: 1348 AN XY: 77348

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0959

Gnomad SAS exome AF: 0.00586

Gnomad FIN exome AF: 0.0000868

Gnomad NFE exome AF: 0.000946

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00744 AC: 10364 AN: 1392940 Hom.: 456 Cov.: 31 AF XY: 0.00704 AC XY: 4839 AN XY: 687336

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.000755

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.00517

Gnomad4 FIN exome AF: 0.0000932

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0363 AC: 5524 AN: 152280 Hom.: 271 Cov.: 33 AF XY: 0.0371 AC XY: 2763 AN XY: 74474

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0347

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0959

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.00902 Hom.: 16

Bravo AF: 0.0449

Asia WGS AF: 0.0390 AC: 137 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	Ala398Ala in exon 10 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 11.5% (23/200) of Ha n Chinese chromosomes from a broad population by the 1000 Genomes Project (http: //www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs61731248). -
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

May 17, 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	-0.44
Cadd	Benign	2.5
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61731248; hg19: chr11-17580653; COSMIC: COSV68038480; COSMIC: COSV68038480;