rs113745835

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.2098G>A(p.Ala700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,548,268 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 8 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.461

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014062047).

BP6

Variant 11-17573095-G-A is Benign according to our data. Variant chr11-17573095-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00433 (659/152254) while in subpopulation AFR AF = 0.0147 (610/41560). AF 95% confidence interval is 0.0137. There are 5 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2098G>A	p.Ala700Thr	missense_variant	Exon 19 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.2134G>A	p.Ala712Thr	missense_variant	Exon 18 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.2098G>A	p.Ala700Thr	missense_variant	Exon 19 of 56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 link	c.2134G>A	p.Ala712Thr	missense_variant	Exon 18 of 55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

653

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00113

AC:

164

AN:

145464

AF XY:

0.000803

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000555

Gnomad OTH exome

AF:

0.000939

GnomAD4 exome

AF:

0.000489

AC:

683

AN:

1396014

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

280

AN XY:

688660

show subpopulations

African (AFR)

AF:

0.0142

AC:

448

AN:

31588

American (AMR)

AF:

0.00140

AC:

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.00199

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46058

Middle Eastern (MID)

AF:

0.000878

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

1078882

Other (OTH)

AF:

0.00174

AC:

101

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00433

AC:

659

AN:

152254

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0147

AC:

610

AN:

41560

American (AMR)

AF:

0.00196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00512

Hom.:

Bravo

AF:

0.00495

ExAC

AF:

0.00110

AC:

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BP4, BS1, BS2 -

Nov 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala712Thr in exon 18 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 1.6% (15/918) of African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs113745835). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.093

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.46

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.95

N;.

REVEL

Benign

0.20

Sift

Benign

0.083

T;.

Sift4G

Benign

0.075

T;T

Vest4

0.050

MVP

0.27

ClinPred

0.017

GERP RS

-9.8

Varity_R

0.076

gMVP

0.31

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over