rs74921579

chr11-17558600-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001292063.2(OTOG):c.1059C>T(p.Val353=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00071 in 1,550,458 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.80

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 11-17558600-C-T is Benign according to our data. Variant chr11-17558600-C-T is described in ClinVar as [Benign]. Clinvar id is 226859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.8 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1059C>T	p.Val353=	synonymous_variant	10/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1095C>T	p.Val365=	synonymous_variant	9/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1059C>T	p.Val353=	synonymous_variant	10/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1095C>T	p.Val365=	synonymous_variant	9/55	5		A2
OTOG	ENST00000485669.1	n.543C>T		non_coding_transcript_exon_variant	3/3	4
OTOG	ENST00000498332.5	n.965C>T		non_coding_transcript_exon_variant	9/16	5

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 532 AN: 152248 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000578 AC: 85 AN: 147052 Hom.: 1 AF XY: 0.000517 AC XY: 41 AN XY: 79336

Gnomad AFR exome AF: 0.00902

Gnomad AMR exome AF: 0.000529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000735

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.000406 AC: 567 AN: 1398092 Hom.: 8 Cov.: 33 AF XY: 0.000384 AC XY: 265 AN XY: 689568

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000980

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000473

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00350 AC: 534 AN: 152366 Hom.: 6 Cov.: 33 AF XY: 0.00326 AC XY: 243 AN XY: 74510

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00396

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Val365Val in exon 9 of OTOG: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 3.4% (6/176) of Yorub a (Nigerian) chromosomes from a broad population by the 1000 Genomes Project (ht tp://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs74921579). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 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	-0.30
Cadd	Benign	14
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs74921579; hg19: chr11-17580147;