rs141010212

chr11-17574824-G-Achr11-17574824-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.2398G>A(p.Asp800Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,550,332 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D800H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.515

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00420323).
• BP6: Variant 11-17574824-G-A is Benign according to our data. Variant chr11-17574824-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17574824-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2398G>A	p.Asp800Asn	missense_variant	20/56	ENST00000399397.6
OTOG	NM_001277269.2	c.2434G>A	p.Asp812Asn	missense_variant	19/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2398G>A	p.Asp800Asn	missense_variant	20/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2434G>A	p.Asp812Asn	missense_variant	19/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152238 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00926

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000572 AC: 85 AN: 148710 Hom.: 0 AF XY: 0.000401 AC XY: 32 AN XY: 79892

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 338 AN: 1397976 Hom.: 2 Cov.: 33 AF XY: 0.000210 AC XY: 145 AN XY: 689466

Gnomad4 AFR exome AF: 0.00908

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000148

Gnomad4 OTH exome AF: 0.000379

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152356 Hom.: 2 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74488

Gnomad4 AFR AF: 0.00921

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000333 Hom.: 0

Bravo AF: 0.00309

ExAC AF: 0.000417 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	OTOG: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	p.Asp812Asn in exon 19 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (184/17160) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs141010212). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2017	- -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 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	0.078
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.8
Dann	Benign	0.77
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N;.
REVEL	Benign	0.019
Sift	Benign	0.22	T;.
Sift4G	Benign	0.98	T;T
Vest4		0.061
MVP		0.040
ClinPred		0.0042	T
GERP RS		-3.8
Varity_R		0.026
gMVP		0.46

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: rs141010212; hg19: chr11-17596371; COSMIC: COSV105230640; COSMIC: COSV105230640;