rs193083374

Positions:

• chr11-17610535-C-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.5235C>A​(p.Leu1745=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 1,550,622 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (80 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.575

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=-0.74).
• BP6: Variant 11-17610535-C-A is Benign according to our data. Variant chr11-17610535-C-A is described in ClinVar as [Benign]. Clinvar id is 226896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17610535-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.575 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.5235C>A	p.Leu1745=	synonymous_variant	36/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.5271C>A	p.Leu1757=	synonymous_variant	35/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.5235C>A	p.Leu1745=	synonymous_variant	36/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.5271C>A	p.Leu1757=	synonymous_variant	35/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.2573C>A		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1037 AN: 152138 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00913

GnomAD3 exomes AF: 0.00601 AC: 894 AN: 148860 Hom.: 6 AF XY: 0.00607 AC XY: 486 AN XY: 80118

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00687

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00812

GnomAD4 exome AF: 0.00967 AC: 13526 AN: 1398366 Hom.: 80 Cov.: 63 AF XY: 0.00956 AC XY: 6596 AN XY: 689708

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00590

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.00680 AC: 1036 AN: 152256 Hom.: 8 Cov.: 33 AF XY: 0.00648 AC XY: 482 AN XY: 74436

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00903

Alfa AF: 0.00910 Hom.: 6

Bravo AF: 0.00672

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOG: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu1757Leu in exon 35 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 2.9% (5/170) of Eur opean American chromosomes from a broad population by the 1000 Genomes Project ( http://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs193083374). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.82
DANN	Benign	0.51

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: rs193083374; hg19: chr11-17632082;