Genetic Variant OTOGL:p.Ile1062Val (chr12-80302754-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378609.3(OTOGL):c.3184A>G(p.Ile1062Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000727 in 1,376,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1062F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.69

Publications

0 publications found

Variant links:

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 84B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11184016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.3184A>G	p.Ile1062Val	missense_variant	Exon 28 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 link	c.3184A>G	p.Ile1062Val	missense_variant	Exon 28 of 59	5	NM_001378609.3	ENSP00000447211.2		Q3ZCN5
OTOGL	ENST00000646859.1 link	c.3049A>G	p.Ile1017Val	missense_variant	Exon 32 of 63			ENSP00000496036.1		A0A2R8YF04

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1376138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31296

American (AMR)

AF:

0.00

AC:

AN:

36894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24226

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37326

South Asian (SAS)

AF:

0.00

AC:

AN:

72592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074282

Other (OTH)

AF:

0.00

AC:

AN:

57388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.60

Eigen

Benign

-0.087

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.79

T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

0.030

.;.;N

REVEL

Benign

0.11

Sift

Benign

1.0

.;.;T

Sift4G

Benign

0.42

.;.;T

Vest4

0.11

MutPred

0.57

.;.;Loss of ubiquitination at K1056 (P = 0.0896);

MVP

0.12

MPC

0.025

ClinPred

0.16

GERP RS

4.5

gMVP

0.28

Mutation Taster

=77/23

polymorphism

(source)

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

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chr12-80302754-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over