Genetic Variant NM_001378609.3:c.5545A>T (chr12-80353462-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001378609.3(OTOGL):c.5545A>T(p.Ile1849Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1849V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.979

Publications

28 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41612947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	NM_001378609.3	MANE Select	c.5545A>T	p.Ile1849Phe	missense	Exon 46 of 59	NP_001365538.2
OTOGL	NM_001378610.3		c.5545A>T	p.Ile1849Phe	missense	Exon 49 of 62	NP_001365539.2
OTOGL	NM_173591.7		c.5545A>T	p.Ile1849Phe	missense	Exon 46 of 59	NP_775862.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5545A>T	p.Ile1849Phe	missense	Exon 46 of 59	ENSP00000447211.2
OTOGL	ENST00000646859.1		c.5410A>T	p.Ile1804Phe	missense	Exon 50 of 63	ENSP00000496036.1
OTOGL	ENST00000298820.7	TSL:5	c.844A>T	p.Ile282Phe	missense	Exon 7 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1448868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719370

African (AFR)

AF:

0.00

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

42954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

83596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105292

Other (OTH)

AF:

0.00

AC:

AN:

59972

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

192539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.00074

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.066

MetaRNN

Benign

0.42

MetaSVM

Uncertain

-0.062

PhyloP100

0.98

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.55

Sift

Benign

0.071

Sift4G

Uncertain

0.0040

Vest4

0.66

MutPred

0.67

Gain of ubiquitination at K1836 (P = 0.1446)

MVP

0.36

MPC

0.14

ClinPred

0.83

GERP RS

0.80

gMVP

0.78

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over