11-17553161-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001292063.2(OTOG):c.335C>G(p.Ala112Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000722 in 1,550,568 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.85

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024275392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.335C>G	p.Ala112Gly	missense_variant	5/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.371C>G	p.Ala124Gly	missense_variant	4/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.335C>G	p.Ala112Gly	missense_variant	5/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.371C>G	p.Ala124Gly	missense_variant	4/55	5		A2	Q6ZRI0-1
OTOG	ENST00000428619.1 linkuse as main transcript	c.152C>G	p.Ala51Gly	missense_variant	3/4	3
OTOG	ENST00000498332.5 linkuse as main transcript	n.241C>G		non_coding_transcript_exon_variant	4/16	5

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000479

AC:

AN:

148206

Hom.:

AF XY:

0.000363

AC XY:

AN XY:

79860

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.0000715

AC:

100

AN:

1398252

Hom.:

Cov.:

AF XY:

0.0000667

AC XY:

AN XY:

689652

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.00216

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000139

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000159

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 31, 2015

The p.Ala124Gly variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation a nalyses suggest that the p.Ala124Gly variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala124Gly variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.18

DEOGEN2

Benign

0.024

T;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.62

T;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.024

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

L;.;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

2.1

N;.;.

REVEL

Benign

0.10

Sift

Benign

1.0

T;.;.

Sift4G

Benign

0.35

T;T;T

Vest4

0.25

MVP

0.092

ClinPred

0.015

GERP RS

4.4

Varity_R

0.062

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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