rs575344158

Positions:

• chr11-17558591-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001292063.2(OTOG):​c.1050C>T​(p.His350=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,550,464 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.370

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-17558591-C-T is Benign according to our data. Variant chr11-17558591-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 514533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.37 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.1050C>T	p.His350=	synonymous_variant	10/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.1086C>T	p.His362=	synonymous_variant	9/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.1050C>T	p.His350=	synonymous_variant	10/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.1086C>T	p.His362=	synonymous_variant	9/55	5		ENSP00000382323	A2
OTOG	ENST00000485669.1	n.534C>T		non_coding_transcript_exon_variant	3/3	4
OTOG	ENST00000498332.5	n.956C>T		non_coding_transcript_exon_variant	9/16	5

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000850 AC: 125 AN: 147066 Hom.: 0 AF XY: 0.000958 AC XY: 76 AN XY: 79340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.00454

Gnomad EAS exome AF: 0.0000927

Gnomad SAS exome AF: 0.000799

Gnomad FIN exome AF: 0.00215

Gnomad NFE exome AF: 0.000478

Gnomad OTH exome AF: 0.000469

GnomAD4 exome AF: 0.000514 AC: 719 AN: 1398114 Hom.: 1 Cov.: 33 AF XY: 0.000500 AC XY: 345 AN XY: 689588

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.00492

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.000682

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.000707

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74496

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000793 Hom.: 0

Bravo AF: 0.000310

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	OTOG: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2017

p.His362His in exon 9 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has also been identified in 0.4% (35/8398) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs575344158). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.4
DANN	Benign	0.79

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: rs575344158; hg19: chr11-17580138;