rs56359117

Positions:

• chr11-17593697-A-G
• chr11-17593697-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001292063.2(OTOG):​c.3229A>G​(p.Ile1077Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,548,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 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 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.569

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010198325).
• BP6: Variant 11-17593697-A-G is Benign according to our data. Variant chr11-17593697-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517484.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr11-17593697-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3229A>G	p.Ile1077Val	missense_variant	27/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3265A>G	p.Ile1089Val	missense_variant	26/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3229A>G	p.Ile1077Val	missense_variant	27/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3265A>G	p.Ile1089Val	missense_variant	26/55	5		A2
OTOG	ENST00000342528.2	n.594A>G		non_coding_transcript_exon_variant	4/22	2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000768 AC: 114 AN: 148440 Hom.: 0 AF XY: 0.000787 AC XY: 63 AN XY: 80016

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.00203

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000887

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000768 AC: 1073 AN: 1396700 Hom.: 1 Cov.: 32 AF XY: 0.000749 AC XY: 516 AN XY: 688890

Gnomad4 AFR exome AF: 0.000222

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0000415

Gnomad4 NFE exome AF: 0.000804

Gnomad4 OTH exome AF: 0.000588

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74456

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000476 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1089 of the OTOG protein (p.Ile1089Val). This variant is present in population databases (rs56359117, 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: 517484). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2017

p.Ile1089Val in exon 26 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 7 mammals have a valine (Val) at this position despite high nearby amino a cid conservation. In addition, computational prediction tools do not suggest a h igh likelihood of impact to the protein. It has also been identified in 0.2% (16 /8400) of Ashkenazi Jewish chromosomes and 0.07% (125/173696) of total chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs56359117). -

OTOG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

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	0.084
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	0.54	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N;.
REVEL	Benign	0.030
Sift	Benign	0.13	T;.
Sift4G	Benign	0.30	T;T
Vest4		0.11
MVP		0.17
ClinPred		0.0042	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs56359117; hg19: chr11-17615244;