rs117380920

chr11-17609906-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.4606C>T(p.Leu1536Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,521,602 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (87 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.469

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030214787).
• BP6: Variant 11-17609906-C-T is Benign according to our data. Variant chr11-17609906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4606C>T	p.Leu1536Phe	missense_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4642C>T	p.Leu1548Phe	missense_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4606C>T	p.Leu1536Phe	missense_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4642C>T	p.Leu1548Phe	missense_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.1944C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1215 AN: 151962 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00201

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00823 AC: 1023 AN: 124278 Hom.: 5 AF XY: 0.00822 AC XY: 535 AN XY: 65124

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00825

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00318

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0110 AC: 15009 AN: 1369522 Hom.: 87 Cov.: 31 AF XY: 0.0110 AC XY: 7365 AN XY: 671574

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00913

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.00967

GnomAD4 genome AF: 0.00798 AC: 1213 AN: 152080 Hom.: 9 Cov.: 32 AF XY: 0.00772 AC XY: 574 AN XY: 74336

Gnomad4 AFR AF: 0.00198

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0105 Hom.: 4

Bravo AF: 0.00907

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0112 AC: 43

ExAC AF: 0.00389 AC: 112

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	OTOG: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Leu1548Phe in exon 35 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 4.2% (5/120) of Colombian chromosome s from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.g ov/projects/SNP; dbSNP rs117380920). -

Meniere disease Benign:1

Likely benign, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.98	N;.
REVEL	Benign	0.040
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.056	T;D
Vest4		0.045
MVP		0.095
ClinPred		0.0042	T
GERP RS		2.4
Varity_R		0.068
gMVP		0.28

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: rs117380920; hg19: chr11-17631453; COSMIC: COSV99063455;