Genetic Variant OTOGL:c.4744-6_4744-5dupTT (chr12-80336781-C-CTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001378609.3(OTOGL):c.4744-6_4744-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOGL
NM_001378609.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.465

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.4744-6_4744-5dupTT		splice_region_variant, intron_variant	Intron 40 of 58	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOGL	ENST00000547103.7 link	c.4744-16_4744-15insTT	intron_variant	Intron 40 of 58	5	NM_001378609.3	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1 link	c.4609-16_4609-15insTT	intron_variant	Intron 44 of 62			ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7 link	c.43-16_43-15insTT	intron_variant	Intron 1 of 17	5		ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147876

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD2 exomes

AF:

0.000148

AC:

AN:

74216

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000284

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1092888

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

541102

show subpopulations

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

African (AFR)

AF:

0.000123

AC:

AN:

24470

American (AMR)

AF:

0.000175

AC:

AN:

28518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19798

East Asian (EAS)

AF:

0.00

AC:

AN:

26192

South Asian (SAS)

AF:

0.0000802

AC:

AN:

62340

European-Finnish (FIN)

AF:

0.0000268

AC:

AN:

37356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

844362

Other (OTH)

AF:

0.00

AC:

AN:

45814

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71990

African (AFR)

AF:

0.00

AC:

AN:

40502

American (AMR)

AF:

0.00

AC:

AN:

14840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

5056

South Asian (SAS)

AF:

0.00

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66612

Other (OTH)

AF:

0.00

AC:

AN:

2006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over