rs147355325

Positions:

• chr11-17560763-T-G

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.1397T>G​(p.Phe466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000384 in 1,550,706 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.67

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=0.0073337257).
• BP6: Variant 11-17560763-T-G is Benign according to our data. Variant chr11-17560763-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 227765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1397T>G	p.Phe466Cys	missense_variant	13/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1433T>G	p.Phe478Cys	missense_variant	12/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1397T>G	p.Phe466Cys	missense_variant	13/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1433T>G	p.Phe478Cys	missense_variant	12/55	5		A2
OTOG	ENST00000498332.5	n.1303T>G		non_coding_transcript_exon_variant	12/16	5

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152140 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000393 AC: 59 AN: 150022 Hom.: 0 AF XY: 0.000310 AC XY: 25 AN XY: 80664

Gnomad AFR exome AF: 0.00712

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000198 AC: 277 AN: 1398448 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 129 AN XY: 689758

Gnomad4 AFR exome AF: 0.00598

Gnomad4 AMR exome AF: 0.000616

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.00210 AC: 319 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74450

Gnomad4 AFR AF: 0.00693

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00249

ExAC AF: 0.000251 AC: 7

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely 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	Invitae	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 22, 2017

p.Phe478Cys in exon 12 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (108/15306) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs147355325). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 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
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	0.77	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0090	D;D
Vest4		0.56
MVP		0.45
ClinPred		0.052	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.77

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: rs147355325; hg19: chr11-17582310;