rs189910531

Positions:

• chr11-17641026-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001292063.2(OTOG):​c.8125G>A​(p.Asp2709Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00037 in 1,417,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 6.70

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020392388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.8125G>A	p.Asp2709Asn	missense_variant	51/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.8161G>A	p.Asp2721Asn	missense_variant	50/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.8125G>A	p.Asp2709Asn	missense_variant	51/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.8161G>A	p.Asp2721Asn	missense_variant	50/55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.000853 AC: 123 AN: 144264 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000379

Gnomad OTH AF: 0.00100

GnomAD3 exomes AF: 0.000273 AC: 40 AN: 146344 Hom.: 0 AF XY: 0.000278 AC XY: 22 AN XY: 79046

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.000529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000693

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000934

GnomAD4 exome AF: 0.000316 AC: 402 AN: 1272990 Hom.: 0 Cov.: 35 AF XY: 0.000299 AC XY: 187 AN XY: 626408

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.0000487

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.0000286

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.000541

GnomAD4 genome AF: 0.000852 AC: 123 AN: 144368 Hom.: 0 Cov.: 32 AF XY: 0.000986 AC XY: 69 AN XY: 69950

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00160

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000379

Gnomad4 OTH AF: 0.000992

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000946 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 23, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2721 of the OTOG protein (p.Asp2721Asn). This variant is present in population databases (rs189910531, gnomAD 0.2%). 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: 504840). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 18B Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 26, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2017

The p.Asp2721Asn variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 1/868 of African chromosomes and 1/272 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs189910531). Although this variant has been seen in t he general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein. In summary, the clinical significance of the p.Asp2721Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Benign	0.20
Sift	Benign	0.072	T;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.58
MVP		0.15
ClinPred		0.060	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs189910531; hg19: chr11-17662573;