chr12-80262052-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378609.3(OTOGL):c.1973A>T(p.His658Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00236 in 1,612,944 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H658R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 112 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.79

Publications

8 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=0.0025278926).

BP6

Variant 12-80262052-A-T is Benign according to our data. Variant chr12-80262052-A-T is described in ClinVar as Benign. ClinVar VariationId is 226929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.1973A>T	p.His658Leu	missense_variant	Exon 19 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOGL	ENST00000547103.7 link	c.1973A>T	p.His658Leu	missense_variant	Exon 19 of 59	5	NM_001378609.3	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1 link	c.1973A>T	p.His658Leu	missense_variant	Exon 24 of 63			ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000643417.1 link	n.2633A>T		non_coding_transcript_exon_variant	Exon 22 of 23

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

477

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0740

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00640

AC:

1577

AN:

246388

AF XY:

0.00597

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.0710

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000815

Gnomad OTH exome

AF:

0.00398

GnomAD4 exome

AF:

0.00228

AC:

3335

AN:

1460654

Hom.:

112

Cov.:

AF XY:

0.00224

AC XY:

1630

AN XY:

726598

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33434

American (AMR)

AF:

0.00507

AC:

226

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00245

AC:

AN:

26102

East Asian (EAS)

AF:

0.0635

AC:

2518

AN:

39642

South Asian (SAS)

AF:

0.00152

AC:

131

AN:

86176

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000810

AC:

AN:

1111222

Other (OTH)

AF:

0.00486

AC:

293

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

169

337

506

674

843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00312

AC:

475

AN:

152290

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41572

American (AMR)

AF:

0.00216

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.0738

AC:

382

AN:

5176

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00360

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00608

AC:

735

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 27, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His649Leu in exon 18 of OTOGL: This variant is not expected to have clinical sig nificance because it has been identified in 6.5% (13/200) of Han Chinese chromos omes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.ni h.gov/projects/SNP; dbSNP rs79711087). -

not provided

Benign:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;.;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.94

PhyloP100

5.8

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.4

.;.;D

REVEL

Benign

0.16

Sift

Benign

0.56

.;.;T

Sift4G

Benign

0.27

.;.;T

Vest4

0.47

MVP

0.29

MPC

0.057

ClinPred

0.034

GERP RS

4.2

gMVP

0.46

Mutation Taster

=88/12

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