rs116947228

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292063.2(OTOG):c.3674G>A(p.Arg1225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,549,584 control chromosomes in the GnomAD database, including 200 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 169 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.718

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023708344).

BP6

Variant 11-17596999-G-A is Benign according to our data. Variant chr11-17596999-G-A is described in ClinVar as Benign. ClinVar VariationId is 226890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0851 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.3674G>A	p.Arg1225His	missense	Exon 30 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3710G>A	p.Arg1237His	missense	Exon 29 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.3674G>A	p.Arg1225His	missense	Exon 30 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.3710G>A	p.Arg1237His	missense	Exon 29 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2	TSL:2	n.1039G>A		non_coding_transcript_exon	Exon 7 of 22

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

826

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0922

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00837

AC:

1242

AN:

148472

AF XY:

0.00808

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.000367

Gnomad ASJ exome

AF:

0.00144

Gnomad EAS exome

AF:

0.0840

Gnomad FIN exome

AF:

0.00819

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.00419

GnomAD4 exome

AF:

0.00436

AC:

6099

AN:

1397336

Hom.:

169

Cov.:

AF XY:

0.00427

AC XY:

2946

AN XY:

689234

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

31590

American (AMR)

AF:

0.000420

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00135

AC:

AN:

25152

East Asian (EAS)

AF:

0.0908

AC:

3245

AN:

35734

South Asian (SAS)

AF:

0.00249

AC:

197

AN:

79200

European-Finnish (FIN)

AF:

0.00855

AC:

410

AN:

47936

Middle Eastern (MID)

AF:

0.000546

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00167

AC:

1804

AN:

1078596

Other (OTH)

AF:

0.00647

AC:

375

AN:

57938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

320

640

959

1279

1599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00541

AC:

824

AN:

152248

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41552

American (AMR)

AF:

0.000720

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.0919

AC:

475

AN:

5170

South Asian (SAS)

AF:

0.00456

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00185

AC:

126

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00408

Hom.:

Bravo

AF:

0.00472

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00397

AC:

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

0.72

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

REVEL

Benign

0.090

Sift

Benign

0.21

Sift4G

Uncertain

0.0080

Vest4

0.16

MVP

0.24

ClinPred

0.0037

GERP RS

1.8

Varity_R

0.041

gMVP

0.44

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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