12-80370580-C-T

Position:

chr12-80370580-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378609.3(OTOGL):c.6626C>T(p.Thr2209Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000771 in 1,534,932 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 7 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.87

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:

OTOGL (HGNC:):

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012212127).

BP6

Variant 12-80370580-C-T is Benign according to our data. Variant chr12-80370580-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80370580-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00178 (270/151882) while in subpopulation AFR AF= 0.00398 (165/41462). AF 95% confidence interval is 0.00348. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.6626C>T	p.Thr2209Ile	missense_variant	56/59	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.6626C>T	p.Thr2209Ile	missense_variant	56/59	5	NM_001378609.3	ENSP00000447211.2		Q3ZCN5

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00283

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000737

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.000987

AC:

199

AN:

201562

Hom.:

AF XY:

0.000962

AC XY:

106

AN XY:

110144

show subpopulations

Gnomad AFR exome

AF:

0.00485

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.000762

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000743

Gnomad OTH exome

AF:

0.00240

GnomAD4 exome

AF:

0.000660

AC:

913

AN:

1383050

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

447

AN XY:

686818

show subpopulations

Gnomad4 AFR exome

AF:

0.00468

Gnomad4 AMR exome

AF:

0.00252

Gnomad4 ASJ exome

AF:

0.000555

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000978

Gnomad4 FIN exome

AF:

0.0000391

Gnomad4 NFE exome

AF:

0.000478

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.00178

AC:

270

AN:

151882

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

120

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00398

Gnomad4 AMR

AF:

0.00276

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000737

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.000841

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Thr2200Ile in exon 55 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 4.6% (9/194) of Luhya (Kenyan) chro mosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm .nih.gov/projects/SNP; dbSNP rs146572555). -

OTOGL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

T;.;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

.;.;D;.

REVEL

Benign

0.077

Sift

Uncertain

0.0030

.;.;D;.

Sift4G

Benign

0.081

.;.;T;.

Vest4

0.29

MVP

0.085

MPC

0.024

ClinPred

0.023

GERP RS

0.12

gMVP

0.39

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

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