NM_001378609.3:c.4312A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001378609.3(OTOGL):c.4312A>G(p.Met1438Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.335

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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06343886).

BP6

Variant 12-80329083-A-G is Benign according to our data. Variant chr12-80329083-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 506022.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.4312A>G	p.Met1438Val	missense_variant	Exon 37 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.4312A>G	p.Met1438Val	missense_variant	Exon 37 of 59	5	NM_001378609.3	ENSP00000447211.2		Q3ZCN5
OTOGL	ENST00000646859.1 link	c.4177A>G	p.Met1393Val	missense_variant	Exon 41 of 63			ENSP00000496036.1		A0A2R8YF04

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408878

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699316

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30642

American (AMR)

AF:

0.00

AC:

AN:

30414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22696

East Asian (EAS)

AF:

0.00

AC:

AN:

38810

South Asian (SAS)

AF:

0.00

AC:

AN:

76034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094906

Other (OTH)

AF:

0.00

AC:

AN:

58036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Met1429Val variant in exon 36 OTOGL: This variant is not expected to have clin ical significance due to a lack of conservation across species, including mammal s. Of note, 5 mammals (squirrel, rat, horse, ferret, Tasmanian devil) have a Val ine (Val) at this position despite high nearby amino acid conservation. In addit ion, computational prediction tools do not suggest a high likelihood of impact t o the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.17

(source)

DANN

Benign

0.36

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.27

T;.;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-0.94

PhyloP100

-0.34

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

.;.;N

REVEL

Benign

0.0080

Sift

Benign

0.50

.;.;T

Sift4G

Benign

0.70

.;.;T

Vest4

0.073

MutPred

0.37

.;.;Gain of catalytic residue at M1429 (P = 0.0032);

MVP

0.030

MPC

0.022

ClinPred

0.048

GERP RS

-0.93

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over