rs1551122

Positions:

Variant summary

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

The NM_001378609.3(OTOGL):c.6737A>G(p.Asn2246Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.608 in 1,538,726 control chromosomes in the GnomAD database, including 294,099 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N2246N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.50 ( 22244 hom., cov: 32)

Exomes 𝑓: 0.62 ( 271855 hom. )

Consequence

OTOGL
NM_001378609.3 missense, splice_region

Scores

Splicing: ADA: 0.8902

Clinical Significance

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

Conservation

PhyloP100: 4.50

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=4.559077E-6).

BP6

Variant 12-80372020-A-G is Benign according to our data. Variant chr12-80372020-A-G is described in ClinVar as [Benign]. Clinvar id is 226972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80372020-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 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.6737A>G	p.Asn2246Ser	missense_variant, splice_region_variant	57/59	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.6737A>G	p.Asn2246Ser	missense_variant, splice_region_variant	57/59	5	NM_001378609.3	ENSP00000447211	P1

Frequencies

GnomAD3 genomes

AF:

0.503

AC:

76353

AN:

151816

Hom.:

22245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.635

Gnomad EAS

AF:

0.724

Gnomad SAS

AF:

0.626

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.545

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.545

GnomAD3 exomes

AF:

0.581

AC:

122147

AN:

210322

Hom.:

37632

AF XY:

0.597

AC XY:

68609

AN XY:

114888

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.633

Gnomad EAS exome

AF:

0.697

Gnomad SAS exome

AF:

0.630

Gnomad FIN exome

AF:

0.686

Gnomad NFE exome

AF:

0.636

Gnomad OTH exome

AF:

0.589

GnomAD4 exome

AF:

0.619

AC:

859074

AN:

1386792

Hom.:

271855

Cov.:

AF XY:

0.622

AC XY:

429197

AN XY:

690076

show subpopulations

Gnomad4 AFR exome

AF:

0.170

Gnomad4 AMR exome

AF:

0.405

Gnomad4 ASJ exome

AF:

0.628

Gnomad4 EAS exome

AF:

0.725

Gnomad4 SAS exome

AF:

0.633

Gnomad4 FIN exome

AF:

0.684

Gnomad4 NFE exome

AF:

0.634

Gnomad4 OTH exome

AF:

0.603

GnomAD4 genome

AF:

0.503

AC:

76365

AN:

151934

Hom.:

22244

Cov.:

AF XY:

0.508

AC XY:

37717

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.191

Gnomad4 AMR

AF:

0.474

Gnomad4 ASJ

AF:

0.635

Gnomad4 EAS

AF:

0.724

Gnomad4 SAS

AF:

0.626

Gnomad4 FIN

AF:

0.685

Gnomad4 NFE

AF:

0.637

Gnomad4 OTH

AF:

0.546

Alfa

AF:

0.620

Hom.:

51395

Bravo

AF:

0.469

TwinsUK

AF:

0.640

AC:

2372

ALSPAC

AF:

0.641

AC:

2470

ESP6500AA

AF:

0.215

AC:

948

ESP6500EA

AF:

0.641

AC:

5509

ExAC

AF:

0.584

AC:

70865

Asia WGS

AF:

0.639

AC:

2207

AN:

3452

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	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asn2237Ser in exon 56 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 35.9% (3089/8598) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs1551122). -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.77

T;.;T

MetaRNN

Benign

0.0000046

T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.56

P;P;P

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

.;.;N

REVEL

Benign

0.16

Sift

Benign

0.052

.;.;T

Sift4G

Uncertain

0.056

.;.;T

Vest4

0.17

MPC

0.17

ClinPred

0.021

GERP RS

6.0

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.16

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