rs11024357

Positions:

chr11-17645892-G-C

Variant summary

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

The NM_001292063.2(OTOG):c.8690G>C(p.Trp2897Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,550,390 control chromosomes in the GnomAD database, including 39,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3050 hom., cov: 32)

Exomes 𝑓: 0.22 ( 36252 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.16

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=0.0016483366).

BP6

Variant 11-17645892-G-C is Benign according to our data. Variant chr11-17645892-G-C is described in ClinVar as [Benign]. Clinvar id is 226923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17645892-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.8690G>C	p.Trp2897Ser	missense_variant	56/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.8726G>C	p.Trp2909Ser	missense_variant	55/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.8690G>C	p.Trp2897Ser	missense_variant	56/56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.8726G>C	p.Trp2909Ser	missense_variant	55/55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29999

AN:

152128

Hom.:

3056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.0712

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.187

GnomAD3 exomes

AF:

0.200

AC:

29800

AN:

148742

Hom.:

3352

AF XY:

0.210

AC XY:

16858

AN XY:

80180

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.0682

Gnomad SAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.224

AC:

313121

AN:

1398144

Hom.:

36252

Cov.:

AF XY:

0.226

AC XY:

155598

AN XY:

689584

show subpopulations

Gnomad4 AFR exome

AF:

0.150

Gnomad4 AMR exome

AF:

0.120

Gnomad4 ASJ exome

AF:

0.184

Gnomad4 EAS exome

AF:

0.0899

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.238

Gnomad4 NFE exome

AF:

0.232

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.197

AC:

30000

AN:

152246

Hom.:

3050

Cov.:

AF XY:

0.197

AC XY:

14667

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.153

Gnomad4 AMR

AF:

0.160

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.0714

Gnomad4 SAS

AF:

0.268

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.232

Gnomad4 OTH

AF:

0.187

Alfa

AF:

0.213

Hom.:

1244

Bravo

AF:

0.183

TwinsUK

AF:

0.225

AC:

834

ALSPAC

AF:

0.240

AC:

926

ExAC

AF:

0.205

AC:

4346

Asia WGS

AF:

0.170

AC:

594

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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	Trp2909Ser in exon 55 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 32.1% (9/28) of Spanish (Iberian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs11024357). -

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	- -

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.41

N;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.3

D;.

REVEL

Uncertain

0.31

Sift

Benign

0.29

T;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.27

ClinPred

0.014

GERP RS

5.3

Varity_R

0.54

gMVP

0.36

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