rs11024350

Positions:

• chr11-17635139-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.7645C>T​(p.Leu2549=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,548,856 control chromosomes in the GnomAD database, including 13,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1165 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12634 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29

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=-0.68).
• BP6: Variant 11-17635139-C-T is Benign according to our data. Variant chr11-17635139-C-T is described in ClinVar as [Benign]. Clinvar id is 226911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17635139-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7645C>T	p.Leu2549=	synonymous_variant	46/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7681C>T	p.Leu2561=	synonymous_variant	45/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7645C>T	p.Leu2549=	synonymous_variant	46/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.7681C>T	p.Leu2561=	synonymous_variant	45/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.4606-471C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17885 AN: 151960 Hom.: 1166 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.133 AC: 18923 AN: 141776 Hom.: 1485 AF XY: 0.139 AC XY: 10687 AN XY: 76814

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.131 AC: 183533 AN: 1396778 Hom.: 12634 Cov.: 34 AF XY: 0.134 AC XY: 91989 AN XY: 688866

Gnomad4 AFR exome AF: 0.0809

Gnomad4 AMR exome AF: 0.0709

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.118 AC: 17883 AN: 152078 Hom.: 1165 Cov.: 32 AF XY: 0.119 AC XY: 8827 AN XY: 74336

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.126

Alfa AF: 0.127 Hom.: 1475

Bravo AF: 0.112

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu2561Leu in exon 45 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 18.5% (37/200) of H an Chinese chromosomes from a broad population by the 1000 Genomes Project (http ://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs11024350). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.1
DANN	Benign	0.66

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: rs11024350; hg19: chr11-17656686;