rs548278514

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001292063.2(OTOG):c.7510G>A(p.Ala2504Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,475,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.32

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008938849).

BP6

Variant 11-17634873-G-A is Benign according to our data. Variant chr11-17634873-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227795.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00117 (173/147376) while in subpopulation AFR AF = 0.00394 (160/40580). AF 95% confidence interval is 0.00344. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7510G>A	p.Ala2504Thr	missense	Exon 45 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.7546G>A	p.Ala2516Thr	missense	Exon 44 of 55	NP_001264198.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7510G>A	p.Ala2504Thr	missense	Exon 45 of 56	ENSP00000382329.2
OTOG	ENST00000399391.7	TSL:5	c.7546G>A	p.Ala2516Thr	missense	Exon 44 of 55	ENSP00000382323.2
OTOG	ENST00000342528.2	TSL:2	n.4606-737G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

173

AN:

147246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000404

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00293

GnomAD2 exomes

AF:

0.000232

AC:

AN:

146336

AF XY:

0.000152

show subpopulations

Gnomad AFR exome

AF:

0.00282

Gnomad AMR exome

AF:

0.000489

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.000126

AC:

168

AN:

1328540

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

654402

show subpopulations

African (AFR)

AF:

0.00336

AC:

AN:

29450

American (AMR)

AF:

0.000538

AC:

AN:

33480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22602

East Asian (EAS)

AF:

0.00

AC:

AN:

29768

South Asian (SAS)

AF:

0.0000255

AC:

AN:

78490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.0000348

AC:

AN:

1034658

Other (OTH)

AF:

0.000244

AC:

AN:

53364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00117

AC:

173

AN:

147376

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

71868

show subpopulations

African (AFR)

AF:

0.00394

AC:

160

AN:

40580

American (AMR)

AF:

0.000403

AC:

AN:

14890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

4614

South Asian (SAS)

AF:

0.00

AC:

AN:

4366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66548

Other (OTH)

AF:

0.00290

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000838

Hom.:

Bravo

AF:

0.00127

ExAC

AF:

0.000100

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Benign

-0.023

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.74

M_CAP

Benign

0.041

MetaRNN

Benign

0.0089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.075

PhyloP100

1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.39

REVEL

Benign

0.037

Sift

Benign

0.32

Sift4G

Benign

0.49

Vest4

0.068

MVP

0.21

ClinPred

0.033

GERP RS

4.2

Varity_R

0.030

gMVP

0.32

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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