rs185432248

Positions:

• chr11-17610552-G-A
• chr11-17610552-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001292063.2(OTOG):​c.5252G>A​(p.Arg1751His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,549,836 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005325198).
• BP6: Variant 11-17610552-G-A is Benign according to our data. Variant chr11-17610552-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227784.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.5252G>A	p.Arg1751His	missense_variant	36/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.5288G>A	p.Arg1763His	missense_variant	35/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.5252G>A	p.Arg1751His	missense_variant	36/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.5288G>A	p.Arg1763His	missense_variant	35/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.2590G>A		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 180 AN: 151562 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000854

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00113 AC: 168 AN: 148532 Hom.: 0 AF XY: 0.00104 AC XY: 83 AN XY: 79930

Gnomad AFR exome AF: 0.000294

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.000371

Gnomad SAS exome AF: 0.0000446

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00205 AC: 2860 AN: 1398154 Hom.: 5 Cov.: 66 AF XY: 0.00201 AC XY: 1384 AN XY: 689568

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.000925

Gnomad4 ASJ exome AF: 0.000278

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00166

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00119 AC: 180 AN: 151682 Hom.: 0 Cov.: 33 AF XY: 0.00111 AC XY: 82 AN XY: 74096

Gnomad4 AFR AF: 0.000484

Gnomad4 AMR AF: 0.000853

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.00122

ExAC AF: 0.000507 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1763 of the OTOG protein (p.Arg1763His). This variant is present in population databases (rs185432248, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 227784). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOG: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 25, 2017

p.Arg1763His in exon 35 of OTOG: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, >20 mammals have a Histidine (His) at this position despite high nearby a mino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. It has been identified in 0.16% ( 105/66772) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs185432248). -

OTOG-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2023

This variant is classified as likely 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	0.064
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0010
DANN	Benign	0.56
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.45	N;.
REVEL	Benign	0.027
Sift	Benign	0.89	T;.
Sift4G	Benign	0.42	T;T
Vest4		0.018
MVP		0.014
ClinPred		0.0038	T
GERP RS		-12
Varity_R		0.015
gMVP		0.27

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: rs185432248; hg19: chr11-17632099; COSMIC: COSV61130927;