Genetic Variant OTOGL:c.4744-5dupT (chr12-80336781-C-CT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_001378609.3(OTOGL):c.4744-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,107,664 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 26)

Exomes 𝑓: 0.021 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.465

Publications

2 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
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.

PM2

Variant has high frequency in the EAS (0.0248) population. However there is too low homozygotes in high coverage region: (expected more than 90, got 1).

BP6

Variant 12-80336781-C-CT is Benign according to our data. Variant chr12-80336781-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1987155.Status of the report is criteria_provided_single_submitter, 1 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	UniProt
OTOGL	NM_001378609.3	MANE Select	c.4744-5dupT	splice_region intron	N/A	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.4744-5dupT	splice_region intron	N/A	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.4744-5dupT	splice_region intron	N/A	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.4744-16_4744-15insT	intron	N/A	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.4609-16_4609-15insT	intron	N/A	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7	TSL:5	c.43-16_43-15insT	intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.000298

AC:

AN:

147824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000404

Gnomad ASJ

AF:

0.000294

Gnomad EAS

AF:

0.000791

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00115

Gnomad MID

AF:

0.00993

Gnomad NFE

AF:

0.000120

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0315

AC:

2336

AN:

74216

AF XY:

0.0308

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.0385

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.0542

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0283

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0208

AC:

19939

AN:

959764

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

9680

AN XY:

473672

show subpopulations

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

African (AFR)

AF:

0.0206

AC:

448

AN:

21700

American (AMR)

AF:

0.0239

AC:

615

AN:

25700

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

393

AN:

17218

East Asian (EAS)

AF:

0.0267

AC:

520

AN:

19492

South Asian (SAS)

AF:

0.0222

AC:

1227

AN:

55364

European-Finnish (FIN)

AF:

0.0189

AC:

593

AN:

31436

Middle Eastern (MID)

AF:

0.0150

AC:

AN:

3672

European-Non Finnish (NFE)

AF:

0.0204

AC:

15194

AN:

745360

Other (OTH)

AF:

0.0224

AC:

894

AN:

39822

⚠️ 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: 0.245

Heterozygous variant carriers

3160

6319

9479

12638

15798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

630

1260

1890

2520

3150

<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:

0.000304

AC:

AN:

147900

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

AN XY:

72046

show subpopulations

African (AFR)

AF:

0.000296

AC:

AN:

40596

American (AMR)

AF:

0.000404

AC:

AN:

14856

Ashkenazi Jewish (ASJ)

AF:

0.000294

AC:

AN:

3402

East Asian (EAS)

AF:

0.000793

AC:

AN:

5042

South Asian (SAS)

AF:

0.00

AC:

AN:

4686

European-Finnish (FIN)

AF:

0.00115

AC:

AN:

9538

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000120

AC:

AN:

66584

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00

Hom.:

104

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-80336781-CTTT-CTTTT

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

Computational scores

Splicing

Publications

Other links and lift over