rs61611064

Positions:

Variant summary

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

The NM_001292063.2(OTOG):c.917C>A(p.Ala306Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,550,482 control chromosomes in the GnomAD database, including 19,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. A306T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1488 hom., cov: 32)

Exomes 𝑓: 0.16 ( 17924 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.951

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG 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=8.969605E-4).

BP6

Variant 11-17558236-C-A is Benign according to our data. Variant chr11-17558236-C-A is described in ClinVar as [Benign]. Clinvar id is 226925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17558236-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.917C>A	p.Ala306Asp	missense_variant	9/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.953C>A	p.Ala318Asp	missense_variant	8/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.917C>A	p.Ala306Asp	missense_variant	9/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.953C>A	p.Ala318Asp	missense_variant	8/55	5		A2	Q6ZRI0-1
OTOG	ENST00000498332.5 linkuse as main transcript	n.823C>A		non_coding_transcript_exon_variant	8/16	5
OTOG	ENST00000485669.1 linkuse as main transcript	n.405-226C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19209

AN:

152100

Hom.:

1487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0529

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.0538

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.151

GnomAD3 exomes

AF:

0.144

AC:

21426

AN:

149176

Hom.:

1786

AF XY:

0.149

AC XY:

11958

AN XY:

80348

show subpopulations

Gnomad AFR exome

AF:

0.0470

Gnomad AMR exome

AF:

0.0914

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.0525

Gnomad SAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.156

AC:

217519

AN:

1398264

Hom.:

17924

Cov.:

AF XY:

0.157

AC XY:

108577

AN XY:

689660

show subpopulations

Gnomad4 AFR exome

AF:

0.0523

Gnomad4 AMR exome

AF:

0.0969

Gnomad4 ASJ exome

AF:

0.246

Gnomad4 EAS exome

AF:

0.0395

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.161

Gnomad4 OTH exome

AF:

0.157

GnomAD4 genome

AF:

0.126

AC:

19205

AN:

152218

Hom.:

1488

Cov.:

AF XY:

0.124

AC XY:

9209

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0528

Gnomad4 AMR

AF:

0.119

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.0538

Gnomad4 SAS

AF:

0.179

Gnomad4 FIN

AF:

0.120

Gnomad4 NFE

AF:

0.167

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.141

Hom.:

937

Bravo

AF:

0.119

TwinsUK

AF:

0.153

AC:

566

ALSPAC

AF:

0.156

AC:

602

ExAC

AF:

0.136

AC:

3130

Asia WGS

AF:

0.129

AC:

452

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala318Asp in exon 8 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 23.0% (45/196) of Toscan chromosomes f rom a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/ projects/SNP; dbSNP rs61611064). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.00090

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.44

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.035

Sift

Benign

0.21

T;.

Sift4G

Uncertain

0.060

T;T

Vest4

0.10

ClinPred

0.0030

GERP RS

1.7

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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