rs1396310498

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001292063.2(OTOG):c.494C>A(p.Thr165Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.02

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31009907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.494C>A	p.Thr165Asn	missense_variant	Exon 6 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.530C>A	p.Thr177Asn	missense_variant	Exon 5 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.494C>A	p.Thr165Asn	missense_variant	Exon 6 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.530C>A	p.Thr177Asn	missense_variant	Exon 5 of 55	5		ENSP00000382323.2
OTOG	ENST00000498332.5 link	n.400C>A		non_coding_transcript_exon_variant	Exon 5 of 16	5
OTOG	ENST00000428619.1 link	c.*29C>A		downstream_gene_variant		3		ENSP00000399057.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

80046

AF XY:

0.0000248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000863

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1308186

Hom.:

Cov.:

AF XY:

0.00000157

AC XY:

AN XY:

635292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28590

American (AMR)

AF:

0.00

AC:

AN:

21058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19442

East Asian (EAS)

AF:

0.00

AC:

AN:

34702

South Asian (SAS)

AF:

0.00

AC:

AN:

63654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5278

European-Non Finnish (NFE)

AF:

9.65e-7

AC:

AN:

1036248

Other (OTH)

AF:

0.00

AC:

AN:

54086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr177Asn variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 1/11462 of Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Alth ough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and co nservation analyses do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the p.Thr177Asn variant is u ncertain. -

not provided

Uncertain:1

Feb 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.054

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

D;.

REVEL

Benign

0.23

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.015

D;D

Vest4

0.59

MutPred

0.63

Loss of ubiquitination at K173 (P = 0.1191);.;

MVP

0.20

ClinPred

0.34

GERP RS

2.5

Varity_R

0.15

gMVP

0.50

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over