chr12-80302754-A-T

Position:

chr12-80302754-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001378609.3(OTOGL):c.3184A>T(p.Ile1062Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,528,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.69

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013137221).

BP6

Variant 12-80302754-A-T is Benign according to our data. Variant chr12-80302754-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227819.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.3184A>T	p.Ile1062Phe	missense_variant	28/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 linkuse as main transcript	c.3184A>T	p.Ile1062Phe	missense_variant	28/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1 linkuse as main transcript	c.3049A>T	p.Ile1017Phe	missense_variant	32/63			ENSP00000496036

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00269

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:

0.000168

AC:

AN:

178596

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

97036

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00205

Gnomad SAS exome

AF:

0.0000462

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000219

GnomAD4 exome

AF:

0.0000538

AC:

AN:

1376136

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

681308

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0000413

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ExAC

AF:

0.000160

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 227819). This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. This variant is present in population databases (rs188793584, gnomAD 0.2%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1053 of the OTOGL protein (p.Ile1053Phe). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2016	The I1053F variant in the OTOGL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I1053F variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I1053F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I1053F as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2015

p.Ile1053Phe in exon 27 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 0.51% (16/3110) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs188793584). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.55

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.4

.;.;D

REVEL

Benign

0.27

Sift

Uncertain

0.0040

.;.;D

Sift4G

Uncertain

0.0050

.;.;D

Vest4

0.46

MVP

0.35

MPC

0.14

ClinPred

0.17

GERP RS

4.5

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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