11-17578486-G-A

Position:

chr11-17578486-G-A

Variant summary

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

The NM_001292063.2(OTOG):c.2719G>A(p.Ala907Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,539,508 control chromosomes in the GnomAD database, including 110,619 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 (★★).

Frequency

Genomes: 𝑓 0.32 ( 8488 hom., cov: 33)

Exomes 𝑓: 0.38 ( 102131 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.75

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:

OTOG (HGNC:):

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=0.006000221).

BP6

Variant 11-17578486-G-A is Benign according to our data. Variant chr11-17578486-G-A is described in ClinVar as [Benign]. Clinvar id is 226873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17578486-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 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.2719G>A	p.Ala907Thr	missense_variant	23/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.2755G>A	p.Ala919Thr	missense_variant	22/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.2719G>A	p.Ala907Thr	missense_variant	23/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.2755G>A	p.Ala919Thr	missense_variant	22/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.223G>A		non_coding_transcript_exon_variant	1/22	2

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

48915

AN:

152028

Hom.:

8484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.323

AC:

45053

AN:

139384

Hom.:

7864

AF XY:

0.331

AC XY:

25092

AN XY:

75764

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.384

Gnomad EAS exome

AF:

0.230

Gnomad SAS exome

AF:

0.324

Gnomad FIN exome

AF:

0.382

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.380

AC:

527054

AN:

1387362

Hom.:

102131

Cov.:

AF XY:

0.379

AC XY:

259596

AN XY:

684652

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.196

Gnomad4 ASJ exome

AF:

0.380

Gnomad4 EAS exome

AF:

0.205

Gnomad4 SAS exome

AF:

0.324

Gnomad4 FIN exome

AF:

0.371

Gnomad4 NFE exome

AF:

0.402

Gnomad4 OTH exome

AF:

0.363

GnomAD4 genome

AF:

0.322

AC:

48933

AN:

152146

Hom.:

8488

Cov.:

AF XY:

0.320

AC XY:

23788

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.241

Gnomad4 ASJ

AF:

0.377

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.318

Gnomad4 FIN

AF:

0.368

Gnomad4 NFE

AF:

0.398

Gnomad4 OTH

AF:

0.320

Alfa

AF:

0.358

Hom.:

3656

Bravo

AF:

0.306

TwinsUK

AF:

0.406

AC:

1506

ALSPAC

AF:

0.391

AC:

1506

ExAC

AF:

0.300

AC:

6070

Asia WGS

AF:

0.283

AC:

987

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala919Thr in exon 22 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 42.7% (76/178) of English and Scottis h chromosomes from a broad population by the 1000 Genomes Project (http://www.nc bi.nlm.nih.gov/projects/SNP; dbSNP rs2355466). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	-	- -

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.21

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.82

N;.

REVEL

Benign

0.070

Sift

Benign

0.25

T;.

Sift4G

Benign

0.48

T;T

Vest4

0.037

ClinPred

0.0061

GERP RS

4.9

Varity_R

0.056

gMVP

0.25

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