12-80370580-C-T

Variant names:

Variant summary

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

The NM_001378609.3(OTOGL):c.6626C>T(p.Thr2209Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000771 in 1,534,932 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 7 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.87

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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012212127).

BP6

Variant 12-80370580-C-T is Benign according to our data. Variant chr12-80370580-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226971.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 = 0.00178 (270/151882) while in subpopulation AFR AF = 0.00398 (165/41462). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.6626C>T	p.Thr2209Ile	missense_variant	Exon 56 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 link	c.6626C>T	p.Thr2209Ile	missense_variant	Exon 56 of 59	5	NM_001378609.3	ENSP00000447211.2		Q3ZCN5

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00283

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000737

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.000987

AC:

199

AN:

201562

AF XY:

0.000962

show subpopulations

Gnomad AFR exome

AF:

0.00485

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.000762

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000743

Gnomad OTH exome

AF:

0.00240

GnomAD4 exome

AF:

0.000660

AC:

913

AN:

1383050

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

447

AN XY:

686818

show subpopulations

African (AFR)

AF:

0.00468

AC:

139

AN:

29676

American (AMR)

AF:

0.00252

AC:

AN:

33000

Ashkenazi Jewish (ASJ)

AF:

0.000555

AC:

AN:

23410

East Asian (EAS)

AF:

0.00

AC:

AN:

36742

South Asian (SAS)

AF:

0.0000978

AC:

AN:

71550

European-Finnish (FIN)

AF:

0.0000391

AC:

AN:

51170

Middle Eastern (MID)

AF:

0.00804

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.000478

AC:

514

AN:

1075122

Other (OTH)

AF:

0.00195

AC:

111

AN:

56910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

130

173

216

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:

0.00178

AC:

270

AN:

151882

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

120

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.00398

AC:

165

AN:

41462

American (AMR)

AF:

0.00276

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000737

AC:

AN:

67880

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00109

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr2200Ile in exon 55 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 4.6% (9/194) of Luhya (Kenyan) chro mosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm .nih.gov/projects/SNP; dbSNP rs146572555). -

OTOGL-related disorder

Benign:1

Jul 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

T;.;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.9

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

.;.;D;.

REVEL

Benign

0.077

Sift

Uncertain

0.0030

.;.;D;.

Sift4G

Benign

0.081

.;.;T;.

Vest4

0.29

MVP

0.085

MPC

0.024

ClinPred

0.023

GERP RS

0.12

gMVP

0.39

Mutation Taster

=85/15

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over