chr12-80302784-G-A

Position:

chr12-80302784-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001378609.3(OTOGL):c.3213+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,483,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.24

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02109884 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-80302784-G-A is Pathogenic according to our data. Variant chr12-80302784-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 291138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.3213+1G>A		splice_donor_variant, intron_variant		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.3213+1G>A		splice_donor_variant, intron_variant		5	NM_001378609.3	ENSP00000447211.2		Q3ZCN5
OTOGL	ENST00000646859.1 linkuse as main transcript	c.3078+1G>A		splice_donor_variant, intron_variant				ENSP00000496036.1		A0A2R8YF04

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152160

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000423

AC:

AN:

141782

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

77378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000288

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1331086

Hom.:

Cov.:

AF XY:

0.0000396

AC XY:

AN XY:

656988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000474

Gnomad4 OTH exome

AF:

0.0000542

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000518

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2024	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. This variant is present in population databases (rs370730786, gnomAD 0.007%). This sequence change affects a donor splice site in intron 27 of the OTOGL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). ClinVar contains an entry for this variant (Variation ID: 291138). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2016	- -

Autosomal recessive nonsyndromic hearing loss 84B

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2016

- -

OTOGL-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2023

The OTOGL c.3186+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-80696564-G-A). Variants that disrupt the consensus splice donor site in OTOGL are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.93

Position offset: -1

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