chr12-80353462-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173591.7(OTOGL):c.5545A>G(p.Ile1849Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 1,599,948 control chromosomes in the GnomAD database, including 580,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1849F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.84 ( 53660 hom., cov: 32)

Exomes 𝑓: 0.85 ( 527041 hom. )

Consequence

OTOGL
NM_173591.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.979

Publications

28 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.639731E-7).

BP6

Variant 12-80353462-A-G is Benign according to our data. Variant chr12-80353462-A-G is described in ClinVar as Benign. ClinVar VariationId is 226957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173591.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	NM_001378609.3	MANE Select	c.5545A>G	p.Ile1849Val	missense	Exon 46 of 59	NP_001365538.2
OTOGL	NM_001378610.3		c.5545A>G	p.Ile1849Val	missense	Exon 49 of 62	NP_001365539.2
OTOGL	NM_173591.7		c.5545A>G	p.Ile1849Val	missense	Exon 46 of 59	NP_775862.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5545A>G	p.Ile1849Val	missense	Exon 46 of 59	ENSP00000447211.2
OTOGL	ENST00000646859.1		c.5410A>G	p.Ile1804Val	missense	Exon 50 of 63	ENSP00000496036.1
OTOGL	ENST00000298820.7	TSL:5	c.844A>G	p.Ile282Val	missense	Exon 7 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes

AF:

0.840

AC:

127676

AN:

152040

Hom.:

53654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.843

Gnomad ASJ

AF:

0.848

Gnomad EAS

AF:

0.833

Gnomad SAS

AF:

0.885

Gnomad FIN

AF:

0.820

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.858

Gnomad OTH

AF:

0.843

GnomAD2 exomes

AF:

0.842

AC:

192566

AN:

228682

AF XY:

0.846

show subpopulations

Gnomad AFR exome

AF:

0.806

Gnomad AMR exome

AF:

0.792

Gnomad ASJ exome

AF:

0.845

Gnomad EAS exome

AF:

0.820

Gnomad FIN exome

AF:

0.820

Gnomad NFE exome

AF:

0.859

Gnomad OTH exome

AF:

0.831

GnomAD4 exome

AF:

0.853

AC:

1234764

AN:

1447790

Hom.:

527041

Cov.:

AF XY:

0.854

AC XY:

613917

AN XY:

718828

show subpopulations

African (AFR)

AF:

0.804

AC:

26782

AN:

33298

American (AMR)

AF:

0.801

AC:

34313

AN:

42852

Ashkenazi Jewish (ASJ)

AF:

0.841

AC:

21713

AN:

25816

East Asian (EAS)

AF:

0.818

AC:

32194

AN:

39352

South Asian (SAS)

AF:

0.884

AC:

73765

AN:

83480

European-Finnish (FIN)

AF:

0.826

AC:

43554

AN:

52734

Middle Eastern (MID)

AF:

0.789

AC:

4530

AN:

5740

European-Non Finnish (NFE)

AF:

0.857

AC:

946941

AN:

1104596

Other (OTH)

AF:

0.851

AC:

50972

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8554

17108

25663

34217

42771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21140

42280

63420

84560

105700

<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:

0.839

AC:

127723

AN:

152158

Hom.:

53660

Cov.:

AF XY:

0.840

AC XY:

62484

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.809

AC:

33589

AN:

41510

American (AMR)

AF:

0.843

AC:

12887

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.848

AC:

2945

AN:

3472

East Asian (EAS)

AF:

0.833

AC:

4290

AN:

5152

South Asian (SAS)

AF:

0.885

AC:

4275

AN:

4832

European-Finnish (FIN)

AF:

0.820

AC:

8681

AN:

10582

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.858

AC:

58322

AN:

68008

Other (OTH)

AF:

0.842

AC:

1774

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1023

2047

3070

4094

5117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.849

Hom.:

192539

Bravo

AF:

0.836

TwinsUK

AF:

0.850

AC:

3153

ALSPAC

AF:

0.862

AC:

3324

ESP6500AA

AF:

0.815

AC:

3174

ESP6500EA

AF:

0.860

AC:

7138

ExAC

AF:

0.840

AC:

101149

Asia WGS

AF:

0.856

AC:

2977

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.7

(source)

DANN

Benign

0.84

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.75

MetaRNN

Benign

6.6e-7

MetaSVM

Benign

-0.98

PhyloP100

0.98

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.57

REVEL

Benign

0.085

Sift

Benign

0.26

Sift4G

Benign

0.32

Vest4

0.046

MPC

0.022

ClinPred

0.0050

GERP RS

0.80

gMVP

0.34

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over