rs146781877

chr11-17594109-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001292063.2(OTOG):c.3351G>A(p.Pro1117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,550,540 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (56 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.682

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-17594109-G-A is Benign according to our data. Variant chr11-17594109-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.682 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3351G>A	p.Pro1117=	synonymous_variant	28/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3387G>A	p.Pro1129=	synonymous_variant	27/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3351G>A	p.Pro1117=	synonymous_variant	28/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3387G>A	p.Pro1129=	synonymous_variant	27/55	5		A2
OTOG	ENST00000342528.2	n.716G>A		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 936 AN: 152168 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00687 AC: 1025 AN: 149202 Hom.: 9 AF XY: 0.00647 AC XY: 520 AN XY: 80366

Gnomad AFR exome AF: 0.000888

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.00368

Gnomad FIN exome AF: 0.0343

Gnomad NFE exome AF: 0.00527

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00637 AC: 8903 AN: 1398254 Hom.: 56 Cov.: 32 AF XY: 0.00623 AC XY: 4298 AN XY: 689642

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00118

Gnomad4 ASJ exome AF: 0.00361

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.00372

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.00622

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00615 AC: 936 AN: 152286 Hom.: 8 Cov.: 32 AF XY: 0.00745 AC XY: 555 AN XY: 74460

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.00645

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00485 Hom.: 0

Bravo AF: 0.00346

Asia WGS AF: 0.00260 AC: 9 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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	OTOG: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro1129Pro in exon 27 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 been identified in 1.1% (8/758) of Eur opean chromosomes from a broad population by the 1000 Genomes Project (http://ww w.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs146781877). -

OTOG-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	2.0
Dann	Benign	0.54

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: rs146781877; hg19: chr11-17615656; COSMIC: COSV100696253;