rs528799547

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_001292063.2(OTOG):c.1286G>A(p.Arg429Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,550,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R429W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.89

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008750081).

BP6

Variant 11-17559606-G-A is Benign according to our data. Variant chr11-17559606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.1286G>A	p.Arg429Gln	missense_variant	12/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.1322G>A	p.Arg441Gln	missense_variant	11/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.1286G>A	p.Arg429Gln	missense_variant	12/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.1322G>A	p.Arg441Gln	missense_variant	11/55	5		A2	Q6ZRI0-1
OTOG	ENST00000498332.5 linkuse as main transcript	n.1192G>A		non_coding_transcript_exon_variant	11/16	5

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000825

AC:

124

AN:

150316

Hom.:

AF XY:

0.000755

AC XY:

AN XY:

80752

show subpopulations

Gnomad AFR exome

AF:

0.00188

Gnomad AMR exome

AF:

0.0000813

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000444

Gnomad FIN exome

AF:

0.00289

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000459

GnomAD4 exome

AF:

0.000719

AC:

1006

AN:

1398562

Hom.:

Cov.:

AF XY:

0.000697

AC XY:

481

AN XY:

689794

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00288

Gnomad4 NFE exome

AF:

0.000721

Gnomad4 OTH exome

AF:

0.000672

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152260

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.000937

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000525

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2015

p.Arg441Gln in exon 11 of OTOG: This variant is not expected to have clinical si gnificance because the arginine (Arg) at position 441 is not conserved through s pecies, with five mammals (Egyptian jerboa, brush-tailed rat, cat, tenrec, platy pus) having a glutamine (Gln) at this position. This variant has been identified in 0.43% (7/1632) of Finnish chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs528799547). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.48

N;.

REVEL

Benign

0.063

Sift

Benign

0.22

T;.

Sift4G

Benign

0.40

T;T

Vest4

0.14

MVP

0.30

ClinPred

0.015

GERP RS

1.5

Varity_R

0.052

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

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