rs55881341

chr11-17578506-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):c.2739G>A(p.Ser913=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,537,564 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.589

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-17578506-G-A is Benign according to our data. Variant chr11-17578506-G-A is described in ClinVar as [Benign]. Clinvar id is 226875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1740/152334) while in subpopulation AFR AF= 0.0393 (1635/41584). AF 95% confidence interval is 0.0377. There are 27 homozygotes in gnomad4. There are 814 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2739G>A	p.Ser913=	synonymous_variant	23/56	ENST00000399397.6
OTOG	NM_001277269.2	c.2775G>A	p.Ser925=	synonymous_variant	22/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2739G>A	p.Ser913=	synonymous_variant	23/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2775G>A	p.Ser925=	synonymous_variant	22/55	5		A2
OTOG	ENST00000342528.2	n.243G>A		non_coding_transcript_exon_variant	1/22	2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1734 AN: 152216 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00239 AC: 328 AN: 137092 Hom.: 2 AF XY: 0.00185 AC XY: 138 AN XY: 74556

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000180

Gnomad FIN exome AF: 0.000265

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00112 AC: 1551 AN: 1385230 Hom.: 26 Cov.: 32 AF XY: 0.00100 AC XY: 685 AN XY: 683556

Gnomad4 AFR exome AF: 0.0386

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000574

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.0114 AC: 1740 AN: 152334 Hom.: 27 Cov.: 33 AF XY: 0.0109 AC XY: 814 AN XY: 74490

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00581 Hom.: 0

Bravo AF: 0.0128

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Ser925Ser in exon 22 of OTOG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 3.1% (6/194) of Luhy a (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (http ://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs55881341). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

OTOG-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 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	-0.56
Cadd	Benign	1.2
Dann	Benign	0.84

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: rs55881341; hg19: chr11-17600053;