11-17593656-G-A

Variant names:

• chr11-17593656-G-A
• rs11024333
• NM_001292063.2:c.3188G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.3188G>A​(p.Arg1063Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,548,944 control chromosomes in the GnomAD database, including 19,994 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1063L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1605 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18389 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0500
• Publications: 19 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037749708).
• BP6: Variant 11-17593656-G-A is Benign according to our data. Variant chr11-17593656-G-A is described in ClinVar as Benign. ClinVar VariationId is 226879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.3188G>A	p.Arg1063Gln	missense_variant	Exon 27 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3224G>A	p.Arg1075Gln	missense_variant	Exon 26 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3188G>A	p.Arg1063Gln	missense_variant	Exon 27 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3224G>A	p.Arg1075Gln	missense_variant	Exon 26 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.553G>A		non_coding_transcript_exon_variant	Exon 4 of 22	2

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20776 AN: 152048 Hom.: 1605 Cov.: 32

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.0972

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.151 AC: 22323 AN: 147754 AF XY: 0.156

Gnomad AFR exome AF: 0.0878

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.160 AC: 223638 AN: 1396778 Hom.: 18389 Cov.: 32 AF XY: 0.162 AC XY: 111547 AN XY: 688938

African (AFR) AF: 0.0901 AC: 2843 AN: 31542

American (AMR) AF: 0.0797 AC: 2845 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4623 AN: 25180

East Asian (EAS) AF: 0.191 AC: 6829 AN: 35736

South Asian (SAS) AF: 0.190 AC: 15032 AN: 79162

European-Finnish (FIN) AF: 0.132 AC: 6344 AN: 48150

Middle Eastern (MID) AF: 0.161 AC: 726 AN: 4498

European-Non Finnish (NFE) AF: 0.162 AC: 175034 AN: 1078938

Other (OTH) AF: 0.162 AC: 9362 AN: 57868

GnomAD4 genome AF: 0.137 AC: 20784 AN: 152166 Hom.: 1605 Cov.: 32 AF XY: 0.136 AC XY: 10143 AN XY: 74378

African (AFR) AF: 0.0876 AC: 3636 AN: 41508

American (AMR) AF: 0.0970 AC: 1484 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1057 AN: 5168

South Asian (SAS) AF: 0.200 AC: 963 AN: 4820

European-Finnish (FIN) AF: 0.127 AC: 1351 AN: 10600

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10997 AN: 67980

Other (OTH) AF: 0.138 AC: 292 AN: 2112

Alfa AF: 0.152 Hom.: 6188

Bravo AF: 0.130

TwinsUK AF: 0.156 AC: 579

ALSPAC AF: 0.156 AC: 600

ExAC AF: 0.138 AC: 3142

Asia WGS AF: 0.206 AC: 716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg1075Gln in exon 26 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 21.5% (43/200) of Han Chinese chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs11024333). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.5
DANN	Benign	0.70
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.62	N;.
PhyloP100		0.050
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.29	N;.
REVEL	Benign	0.076
Sift	Benign	0.30	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.069
ClinPred		0.0024	T
GERP RS		-3.4
Varity_R		0.043
gMVP		0.36
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11024333; hg19: chr11-17615203; COSMIC: COSV61128669;