rs7936354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001292063.2(OTOG):c.3350C>T(p.Pro1117Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00757 in 1,550,440 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1117P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 418 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 318 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:6

Conservation

PhyloP100: 5.63

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002730459).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 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.3350C>T	p.Pro1117Leu	missense	Exon 28 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3386C>T	p.Pro1129Leu	missense	Exon 27 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.3350C>T	p.Pro1117Leu	missense	Exon 28 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.3386C>T	p.Pro1129Leu	missense	Exon 27 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2	TSL:2	n.715C>T		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5921

AN:

152080

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.00824

AC:

1230

AN:

149206

AF XY:

0.00658

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.00745

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.0000927

Gnomad FIN exome

AF:

0.0000595

Gnomad NFE exome

AF:

0.000654

Gnomad OTH exome

AF:

0.00765

GnomAD4 exome

AF:

0.00416

AC:

5816

AN:

1398242

Hom.:

318

Cov.:

AF XY:

0.00368

AC XY:

2539

AN XY:

689648

show subpopulations

African (AFR)

AF:

0.138

AC:

4367

AN:

31598

American (AMR)

AF:

0.00815

AC:

291

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.000517

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.0000208

AC:

AN:

48166

Middle Eastern (MID)

AF:

0.00825

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000468

AC:

505

AN:

1078940

Other (OTH)

AF:

0.00940

AC:

545

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

263

526

788

1051

1314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.0389

AC:

5927

AN:

152198

Hom.:

418

Cov.:

AF XY:

0.0375

AC XY:

2788

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.134

AC:

5570

AN:

41500

American (AMR)

AF:

0.0145

AC:

221

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68020

Other (OTH)

AF:

0.0331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

260

520

780

1040

1300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0157

Hom.:

487

Bravo

AF:

0.0450

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00710

AC:

144

Asia WGS

AF:

0.00664

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 (3)

not specified (3)

Meniere disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PhyloP100

5.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.48

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Vest4

0.56

MVP

0.74

ClinPred

0.019

GERP RS

4.6

Varity_R

0.32

gMVP

0.82

Mutation Taster

=85/15

polymorphism (auto)

(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