12-80267318-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001378609.3(OTOGL):c.2456C>T(p.Ser819Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,521,864 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.18

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0106340945).

BP6

Variant 12-80267318-C-T is Benign according to our data. Variant chr12-80267318-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227815.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=4}. Variant chr12-80267318-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.2456C>T	p.Ser819Leu	missense_variant	22/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7 linkuse as main transcript	c.2456C>T	p.Ser819Leu	missense_variant	22/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1 linkuse as main transcript	c.2456C>T	p.Ser819Leu	missense_variant	27/63

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

180

AN:

151666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000862

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000946

AC:

205

AN:

216752

Hom.:

AF XY:

0.00105

AC XY:

123

AN XY:

117528

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.000234

Gnomad ASJ exome

AF:

0.000533

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000342

Gnomad FIN exome

AF:

0.000680

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000578

GnomAD4 exome

AF:

0.00113

AC:

1543

AN:

1370198

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

792

AN XY:

682854

show subpopulations

Gnomad4 AFR exome

AF:

0.0000647

Gnomad4 AMR exome

AF:

0.000195

Gnomad4 ASJ exome

AF:

0.000284

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000332

Gnomad4 FIN exome

AF:

0.00130

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.000687

GnomAD4 genome

AF:

0.00119

AC:

180

AN:

151666

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74090

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.000862

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.000816

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.00183

AC:

ExAC

AF:

0.000979

AC:

118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	OTOGL: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2016

p.Ser810Leu in exon 21 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (94/29798) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199855270). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

OTOGL-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2022

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

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

Cadd

Benign

Dann

Benign

0.96

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.70

T;.;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.95

N;N

PrimateAI

Benign

0.39

Vest4

0.27

MVP

0.10

MPC

0.022

ClinPred

0.024

GERP RS

2.6

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over