rs4756902

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.2561+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,535,456 control chromosomes in the GnomAD database, including 113,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10451 hom., cov: 32)

Exomes 𝑓: 0.38 ( 103338 hom. )

Consequence

OTOG
NM_001292063.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.408

Publications

9 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 (BayesDel_noAF=-0.83).

BP6

Variant 11-17576644-G-A is Benign according to our data. Variant chr11-17576644-G-A is described in ClinVar as Benign. ClinVar VariationId is 226871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2561+14G>A		intron_variant	Intron 21 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.2597+14G>A		intron_variant	Intron 20 of 54		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.2561+14G>A		intron_variant	Intron 21 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.2597+14G>A		intron_variant	Intron 20 of 54	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55806

AN:

151632

Hom.:

10443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.443

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.308

Gnomad FIN

AF:

0.373

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.353

GnomAD2 exomes

AF:

0.337

AC:

50288

AN:

149178

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.373

Gnomad NFE exome

AF:

0.396

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.383

AC:

529857

AN:

1383706

Hom.:

103338

Cov.:

AF XY:

0.382

AC XY:

260795

AN XY:

683272

show subpopulations

African (AFR)

AF:

0.372

AC:

11652

AN:

31322

American (AMR)

AF:

0.206

AC:

7338

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9614

AN:

25098

East Asian (EAS)

AF:

0.248

AC:

8855

AN:

35654

South Asian (SAS)

AF:

0.316

AC:

25005

AN:

79012

European-Finnish (FIN)

AF:

0.374

AC:

18013

AN:

48154

Middle Eastern (MID)

AF:

0.350

AC:

1980

AN:

5660

European-Non Finnish (NFE)

AF:

0.400

AC:

425824

AN:

1065606

Other (OTH)

AF:

0.375

AC:

21576

AN:

57520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

13985

27970

41956

55941

69926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13240

26480

39720

52960

66200

<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:

0.368

AC:

55840

AN:

151750

Hom.:

10451

Cov.:

AF XY:

0.364

AC XY:

26988

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.377

AC:

15597

AN:

41418

American (AMR)

AF:

0.262

AC:

4004

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

1321

AN:

3468

East Asian (EAS)

AF:

0.276

AC:

1421

AN:

5152

South Asian (SAS)

AF:

0.307

AC:

1477

AN:

4806

European-Finnish (FIN)

AF:

0.373

AC:

3925

AN:

10532

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.396

AC:

26852

AN:

67804

Other (OTH)

AF:

0.349

AC:

735

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1829

3657

5486

7314

9143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.378

Hom.:

2231

Bravo

AF:

0.360

Asia WGS

AF:

0.308

AC:

1073

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

2597+14G>A in intron 20 of OTOG: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 43.3% (77/178) of English and Scottish chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs4756902). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.1

(source)

DANN

Benign

0.47

PhyloP100

0.41

Mutation Taster

=100/0

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

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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