rs143495342

Positions:

chr12-80377954-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001378609.3(OTOGL):c.6968G>A(p.Arg2323Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,608,672 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.90

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008599758).

BP6

Variant 12-80377954-G-A is Benign according to our data. Variant chr12-80377954-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504851.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.6968G>A	p.Arg2323Gln	missense_variant	59/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 linkuse as main transcript	c.6968G>A	p.Arg2323Gln	missense_variant	59/59	5	NM_001378609.3	ENSP00000447211	P1

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

244

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00138

AC:

331

AN:

239980

Hom.:

AF XY:

0.00135

AC XY:

175

AN XY:

129542

show subpopulations

Gnomad AFR exome

AF:

0.00147

Gnomad AMR exome

AF:

0.000596

Gnomad ASJ exome

AF:

0.000203

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.00228

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.00158

AC:

2299

AN:

1456534

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1115

AN XY:

723994

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.000545

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00167

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152138

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00213

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00167

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00150

AC:

182

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 25, 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 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

p.Arg2314Gln in exon 58 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 0.3% (148/4656) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs14395342). -

OTOGL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2023

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

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.32

Eigen

Benign

-0.21

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0086

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.51

D;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.22

.;.;N

REVEL

Benign

0.079

Sift

Benign

1.0

.;.;T

Sift4G

Benign

1.0

.;.;T

Vest4

0.069

MVP

0.095

MPC

0.025

ClinPred

0.0091

GERP RS

5.7

gMVP

0.29

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