Genetic Variant OTOGL:p.Ser819Trp (chr12-80267318-C-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.2456C>G(p.Ser819Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. S819L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.18

Publications

3 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=0.23544818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.2456C>G	p.Ser819Trp	missense_variant	Exon 22 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.2456C>G	p.Ser819Trp	missense_variant	Exon 22 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1 link	c.2456C>G	p.Ser819Trp	missense_variant	Exon 27 of 63			ENSP00000496036.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

216752

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682868

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30900

American (AMR)

AF:

0.00

AC:

AN:

41046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24664

East Asian (EAS)

AF:

0.00

AC:

AN:

37410

South Asian (SAS)

AF:

0.00

AC:

AN:

78426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

9.58e-7

AC:

AN:

1043926

Other (OTH)

AF:

0.00

AC:

AN:

56758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

2.2

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.8

.;.;D

REVEL

Benign

0.15

Sift

Benign

0.092

.;.;T

Sift4G

Uncertain

0.0030

.;.;D

Vest4

0.61

MutPred

0.61

.;.;Loss of disorder (P = 0.0402);

MVP

0.14

MPC

0.12

ClinPred

0.94

GERP RS

2.6

gMVP

0.63

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over