rs61978648

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001292063.2(OTOG):c.769G>A(p.Val257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,550,636 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.020 ( 74 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 98 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.12

Publications

3 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), 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032092035).

BP6

Variant 11-17557227-G-A is Benign according to our data. Variant chr11-17557227-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226914.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.769G>A	p.Val257Ile	missense	Exon 8 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.805G>A	p.Val269Ile	missense	Exon 7 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOG	ENST00000399397.6	TSL:5 MANE Select	c.769G>A	p.Val257Ile	missense	Exon 8 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.805G>A	p.Val269Ile	missense	Exon 7 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000485669.1	TSL:4	n.308G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3102

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0568

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.00836

AC:

1248

AN:

149234

AF XY:

0.00737

show subpopulations

Gnomad AFR exome

AF:

0.0628

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00101

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00505

AC:

7065

AN:

1398332

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3384

AN XY:

689684

show subpopulations

African (AFR)

AF:

0.0587

AC:

1855

AN:

31598

American (AMR)

AF:

0.0135

AC:

483

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0169

AC:

425

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000972

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

48196

Middle Eastern (MID)

AF:

0.0193

AC:

110

AN:

5698

European-Non Finnish (NFE)

AF:

0.00318

AC:

3432

AN:

1078978

Other (OTH)

AF:

0.0107

AC:

621

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

448

896

1345

1793

2241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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

AF:

0.0204

AC:

3109

AN:

152304

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1474

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0568

AC:

2359

AN:

41554

American (AMR)

AF:

0.0228

AC:

349

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00400

AC:

272

AN:

68028

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0244

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ExAC

AF:

0.00719

AC:

168

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Meniere disease (1)

OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Benign

0.087

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

3.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.090

REVEL

Benign

0.084

Sift

Benign

0.56

Sift4G

Benign

0.067

Vest4

0.16

MVP

0.20

ClinPred

0.011

GERP RS

4.8

Varity_R

0.026

gMVP

0.40

Mutation Taster

=99/1

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over