rs147843540

Positions:

• chr11-17558324-C-A

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.996+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00952 in 1,550,518 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (77 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.624

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 (BayesDel_noAF=-0.78).
• BP6: Variant 11-17558324-C-A is Benign according to our data. Variant chr11-17558324-C-A is described in ClinVar as [Benign]. Clinvar id is 226858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.996+9C>A		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.1032+9C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.996+9C>A		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1032+9C>A		intron_variant		5		A2
OTOG	ENST00000485669.1	n.405-138C>A		intron_variant, non_coding_transcript_variant		4
OTOG	ENST00000498332.5	n.902+9C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1075 AN: 152212 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00694 AC: 1037 AN: 149360 Hom.: 9 AF XY: 0.00725 AC XY: 582 AN XY: 80238

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00359

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00312

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00692

GnomAD4 exome AF: 0.00978 AC: 13681 AN: 1398188 Hom.: 77 Cov.: 32 AF XY: 0.00959 AC XY: 6613 AN XY: 689588

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00450

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00294

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00806

GnomAD4 genome AF: 0.00705 AC: 1074 AN: 152330 Hom.: 9 Cov.: 33 AF XY: 0.00725 AC XY: 540 AN XY: 74484

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00981 Hom.: 0

Bravo AF: 0.00645

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

1032+9C>A in intron 8 of OTOG: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 1.5% (11/758) of European chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/projects/SN P; dbSNP rs147843540). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147843540; hg19: chr11-17579871;