rs11024353

Positions:

• chr11-17638557-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.7894+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,549,324 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (139 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1298 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004638
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.27

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-17638557-C-T is Benign according to our data. Variant chr11-17638557-C-T is described in ClinVar as [Benign]. Clinvar id is 226912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7894+8C>T		splice_region_variant, intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.7930+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7894+8C>T		splice_region_variant, intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7930+8C>T		splice_region_variant, intron_variant		5		A2
OTOG	ENST00000342528.2	n.4806+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6041 AN: 152078 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0442 AC: 6542 AN: 147882 Hom.: 215 AF XY: 0.0462 AC XY: 3682 AN XY: 79654

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0540

Gnomad SAS exome AF: 0.0848

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0401 AC: 56050 AN: 1397126 Hom.: 1298 Cov.: 30 AF XY: 0.0413 AC XY: 28459 AN XY: 689126

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.0256

Gnomad4 EAS exome AF: 0.0432

Gnomad4 SAS exome AF: 0.0828

Gnomad4 FIN exome AF: 0.0311

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0365

GnomAD4 genome AF: 0.0398 AC: 6051 AN: 152198 Hom.: 139 Cov.: 32 AF XY: 0.0418 AC XY: 3107 AN XY: 74406

Gnomad4 AFR AF: 0.0400

Gnomad4 AMR AF: 0.0525

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.0530

Gnomad4 SAS AF: 0.0871

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0349 Hom.: 42

Bravo AF: 0.0377

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	7930+8C>T in intron 47 of OTOG: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 7.2% (14/194) of Luhya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/proj ects/SNP; dbSNP rs11024353). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs11024353; hg19: chr11-17660104;