11-17594057-C-T

Variant names:

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.3299C>T(p.Ala1100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,550,468 control chromosomes in the GnomAD database, including 760 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1100A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.040 ( 436 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 324 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.92

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024787784).

BP6

Variant 11-17594057-C-T is Benign according to our data. Variant chr11-17594057-C-T is described in ClinVar as Benign. ClinVar VariationId is 226883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 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.3299C>T	p.Ala1100Val	missense	Exon 28 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3335C>T	p.Ala1112Val	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.3299C>T	p.Ala1100Val	missense	Exon 28 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.3335C>T	p.Ala1112Val	missense	Exon 27 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2	TSL:2	n.664C>T		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6061

AN:

152072

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.00837

AC:

1248

AN:

149190

AF XY:

0.00665

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.00761

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.0000927

Gnomad FIN exome

AF:

0.0000595

Gnomad NFE exome

AF:

0.000636

Gnomad OTH exome

AF:

0.00695

GnomAD4 exome

AF:

0.00423

AC:

5920

AN:

1398278

Hom.:

324

Cov.:

AF XY:

0.00375

AC XY:

2583

AN XY:

689658

show subpopulations

African (AFR)

AF:

0.140

AC:

4432

AN:

31598

American (AMR)

AF:

0.00829

AC:

296

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.000757

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.0000208

AC:

AN:

48166

Middle Eastern (MID)

AF:

0.00843

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000465

AC:

502

AN:

1078968

Other (OTH)

AF:

0.00967

AC:

561

AN:

57992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

283

565

848

1130

1413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.0399

AC:

6068

AN:

152190

Hom.:

436

Cov.:

AF XY:

0.0381

AC XY:

2836

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.137

AC:

5704

AN:

41498

American (AMR)

AF:

0.0147

AC:

225

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000809

AC:

AN:

68010

Other (OTH)

AF:

0.0327

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

259

517

776

1034

1293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0313

Hom.:

243

Bravo

AF:

0.0459

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00790

AC:

165

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.030

Sift

Benign

0.15

Sift4G

Benign

0.099

Vest4

0.092

MVP

0.15

ClinPred

0.018

GERP RS

3.5

Varity_R

0.11

gMVP

0.42

Mutation Taster

=99/1

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