rs150426222

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378609.3(OTOGL):c.3356T>C(p.Ile1119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,593,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 6 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.09

Publications

5 publications found

Variant links:

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 84B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008200735).

BP6

Variant 12-80310633-T-C is Benign according to our data. Variant chr12-80310633-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226941.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00192 (293/152342) while in subpopulation AFR AF = 0.00452 (188/41584). AF 95% confidence interval is 0.00399. There are 0 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOGL	NM_001378609.3	MANE Select	c.3356T>C	p.Ile1119Thr	missense	Exon 30 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.3356T>C	p.Ile1119Thr	missense	Exon 33 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.3356T>C	p.Ile1119Thr	missense	Exon 30 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.3356T>C	p.Ile1119Thr	missense	Exon 30 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.3221T>C	p.Ile1074Thr	missense	Exon 34 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

290

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00108

AC:

254

AN:

234348

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.00422

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.000502

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000889

Gnomad OTH exome

AF:

0.00321

GnomAD4 exome

AF:

0.000744

AC:

1072

AN:

1440710

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

530

AN XY:

717540

show subpopulations

African (AFR)

AF:

0.00523

AC:

174

AN:

33300

American (AMR)

AF:

0.00235

AC:

105

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.000345

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.000128

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.0000511

AC:

AN:

39122

Middle Eastern (MID)

AF:

0.00869

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000539

AC:

596

AN:

1106032

Other (OTH)

AF:

0.00208

AC:

125

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00192

AC:

293

AN:

152342

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00452

AC:

188

AN:

41584

American (AMR)

AF:

0.00275

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68026

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00122

Hom.:

Bravo

AF:

0.00223

ESP6500AA

AF:

0.00356

AC:

ESP6500EA

AF:

0.000613

AC:

ExAC

AF:

0.000975

AC:

116

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Benign

0.029

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

M_CAP

Benign

0.011

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.99

PhyloP100

3.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.65

REVEL

Benign

0.031

Sift

Benign

0.39

Sift4G

Benign

0.42

Vest4

0.14

MVP

0.048

MPC

0.024

ClinPred

0.011

GERP RS

5.9

gMVP

0.25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over