rs61978648

chr11-17557227-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001292063.2(OTOG):c.769G>A(p.Val257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,550,636 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (98 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.12

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032092035).
• BP6: Variant 11-17557227-G-A is Benign according to our data. Variant chr11-17557227-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226914.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.769G>A	p.Val257Ile	missense_variant	8/56	ENST00000399397.6
OTOG	NM_001277269.2	c.805G>A	p.Val269Ile	missense_variant	7/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.769G>A	p.Val257Ile	missense_variant	8/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.805G>A	p.Val269Ile	missense_variant	7/55	5		A2
OTOG	ENST00000485669.1	n.308G>A		non_coding_transcript_exon_variant	2/3	4
OTOG	ENST00000498332.5	n.675G>A		non_coding_transcript_exon_variant	7/16	5

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3102 AN: 152186 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.00836 AC: 1248 AN: 149234 Hom.: 24 AF XY: 0.00737 AC XY: 592 AN XY: 80356

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00101

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00505 AC: 7065 AN: 1398332 Hom.: 98 Cov.: 32 AF XY: 0.00491 AC XY: 3384 AN XY: 689684

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000972

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0204 AC: 3109 AN: 152304 Hom.: 74 Cov.: 32 AF XY: 0.0198 AC XY: 1474 AN XY: 74480

Gnomad4 AFR AF: 0.0568

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0103 Hom.: 15

Bravo AF: 0.0244

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00719 AC: 168

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Val269Ile in exon 7 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 7.4% (13/176) of Yoruba (Nigerian) chr omosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nl m.nih.gov/projects/SNP; dbSNP rs61978648). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jan 01, 2020

- -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 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
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	0.087
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.090	N;.
REVEL	Benign	0.084
Sift	Benign	0.56	T;.
Sift4G	Benign	0.067	T;T
Vest4		0.16
MVP		0.20
ClinPred		0.011	T
GERP RS		4.8
Varity_R		0.026
gMVP		0.40

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: rs61978648; hg19: chr11-17578774;