12-80353462-A-G

Position:

chr12-80353462-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378609.3(OTOGL):c.5545A>G(p.Ile1849Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 1,599,948 control chromosomes in the GnomAD database, including 580,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 53660 hom., cov: 32)

Exomes 𝑓: 0.85 ( 527041 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.979

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.639731E-7).

BP6

Variant 12-80353462-A-G is Benign according to our data. Variant chr12-80353462-A-G is described in ClinVar as [Benign]. Clinvar id is 226957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80353462-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.5545A>G	p.Ile1849Val	missense_variant	46/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
OTOGL	ENST00000547103.7 linkuse as main transcript	c.5545A>G	p.Ile1849Val	missense_variant	46/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1 linkuse as main transcript	c.5410A>G	p.Ile1804Val	missense_variant	50/63			ENSP00000496036
OTOGL	ENST00000298820.7 linkuse as main transcript	c.847A>G	p.Ile283Val	missense_variant	7/18	5		ENSP00000298820

Frequencies

GnomAD3 genomes

AF:

0.840

AC:

127676

AN:

152040

Hom.:

53654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.843

Gnomad ASJ

AF:

0.848

Gnomad EAS

AF:

0.833

Gnomad SAS

AF:

0.885

Gnomad FIN

AF:

0.820

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.858

Gnomad OTH

AF:

0.843

GnomAD3 exomes

AF:

0.842

AC:

192566

AN:

228682

Hom.:

81156

AF XY:

0.846

AC XY:

104465

AN XY:

123444

show subpopulations

Gnomad AFR exome

AF:

0.806

Gnomad AMR exome

AF:

0.792

Gnomad ASJ exome

AF:

0.845

Gnomad EAS exome

AF:

0.820

Gnomad SAS exome

AF:

0.886

Gnomad FIN exome

AF:

0.820

Gnomad NFE exome

AF:

0.859

Gnomad OTH exome

AF:

0.831

GnomAD4 exome

AF:

0.853

AC:

1234764

AN:

1447790

Hom.:

527041

Cov.:

AF XY:

0.854

AC XY:

613917

AN XY:

718828

show subpopulations

Gnomad4 AFR exome

AF:

0.804

Gnomad4 AMR exome

AF:

0.801

Gnomad4 ASJ exome

AF:

0.841

Gnomad4 EAS exome

AF:

0.818

Gnomad4 SAS exome

AF:

0.884

Gnomad4 FIN exome

AF:

0.826

Gnomad4 NFE exome

AF:

0.857

Gnomad4 OTH exome

AF:

0.851

GnomAD4 genome

AF:

0.839

AC:

127723

AN:

152158

Hom.:

53660

Cov.:

AF XY:

0.840

AC XY:

62484

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.809

Gnomad4 AMR

AF:

0.843

Gnomad4 ASJ

AF:

0.848

Gnomad4 EAS

AF:

0.833

Gnomad4 SAS

AF:

0.885

Gnomad4 FIN

AF:

0.820

Gnomad4 NFE

AF:

0.858

Gnomad4 OTH

AF:

0.842

Alfa

AF:

0.851

Hom.:

124907

Bravo

AF:

0.836

TwinsUK

AF:

0.850

AC:

3153

ALSPAC

AF:

0.862

AC:

3324

ESP6500AA

AF:

0.815

AC:

3174

ESP6500EA

AF:

0.860

AC:

7138

ExAC

AF:

0.840

AC:

101149

Asia WGS

AF:

0.856

AC:

2977

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile1840Val in exon 45 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 18.5% (722/3896) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs7297767). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.7

DANN

Benign

0.84

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.75

T;.;T

MetaRNN

Benign

6.6e-7

T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.57

.;.;N

REVEL

Benign

0.085

Sift

Benign

0.26

.;.;T

Sift4G

Benign

0.32

.;.;T

Vest4

0.046

MPC

0.022

ClinPred

0.0050

GERP RS

0.80

gMVP

0.34

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

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