chr12-80302784-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021240441 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 VariationId is 291138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	Effect	Exon Rank	Protein
OTOGL	NM_001378609.3	MANE Select	c.3213+1G>A	splice_donor intron	N/A	NP_001365538.2
OTOGL	NM_001378610.3		c.3213+1G>A	splice_donor intron	N/A	NP_001365539.2
OTOGL	NM_173591.7		c.3213+1G>A	splice_donor intron	N/A	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.3213+1G>A		splice_donor intron	N/A	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.3078+1G>A		splice_donor intron	N/A	ENSP00000496036.1

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

GnomAD2 exomes

AF:

0.0000423

AC:

AN:

141782

AF XY:

0.0000517

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 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

African (AFR)

AF:

0.00

AC:

AN:

29254

American (AMR)

AF:

0.00

AC:

AN:

27174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21832

East Asian (EAS)

AF:

0.00

AC:

AN:

36592

South Asian (SAS)

AF:

0.00

AC:

AN:

64686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5308

European-Non Finnish (NFE)

AF:

0.0000474

AC:

AN:

1055564

Other (OTH)

AF:

0.0000542

AC:

AN:

55328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000687

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.0000253

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 84B (2)

Inborn genetic diseases (1)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.2

GERP RS

5.8

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over