rs553479177

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001292063.2(OTOG):c.5051C>T(p.Pro1684Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,550,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0890

Variant links:

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]

OTOG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010405958).

BP6

Variant 11-17610351-C-T is Benign according to our data. Variant chr11-17610351-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227783.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.5051C>T	p.Pro1684Leu	missense_variant	Exon 36 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.5087C>T	p.Pro1696Leu	missense_variant	Exon 35 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.5051C>T	p.Pro1684Leu	missense_variant	Exon 36 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.5087C>T	p.Pro1696Leu	missense_variant	Exon 35 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.2389C>T		non_coding_transcript_exon_variant	Exon 12 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000334

AC:

AN:

149496

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

80440

show subpopulations

Gnomad AFR exome

AF:

0.000146

Gnomad AMR exome

AF:

0.0000407

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:

0.000693

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1398374

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689712

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.000131

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Bravo

AF:

0.000272

ExAC

AF:

0.0000291

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Apr 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro1696Leu in exon 35 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, rabbit, pika, and elephant shrew have a leucine (Leu) at this position. In addition, computational prediction tools do not suggest a high likelihood of im pact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.5

DANN

Benign

0.72

DEOGEN2

Benign

0.038

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.41

N;.

REVEL

Benign

0.062

Sift

Benign

0.16

T;.

Sift4G

Benign

0.19

T;T

Vest4

0.070

MutPred

0.37

Loss of glycosylation at T1697 (P = 0.0408);.;

MVP

0.37

ClinPred

0.015

GERP RS

2.6

Varity_R

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over