rs117462138

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173591.7(OTOGL):c.3427A>G(p.Ile1143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,586,528 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 11 hom. )

Consequence

OTOGL
NM_173591.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.01

Publications

8 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=0.015127599).

BP6

Variant 12-80310704-A-G is Benign according to our data. Variant chr12-80310704-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00238 (362/152286) while in subpopulation NFE AF = 0.0039 (265/68012). AF 95% confidence interval is 0.00351. There are 2 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.3427A>G	p.Ile1143Val	missense	Exon 30 of 59	NP_001365538.2
OTOGL	NM_001378610.3		c.3427A>G	p.Ile1143Val	missense	Exon 33 of 62	NP_001365539.2
OTOGL	NM_173591.7		c.3427A>G	p.Ile1143Val	missense	Exon 30 of 59	NP_775862.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.3427A>G	p.Ile1143Val	missense	Exon 30 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.3292A>G	p.Ile1098Val	missense	Exon 34 of 63	ENSP00000496036.1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00268

AC:

628

AN:

234398

AF XY:

0.00269

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00772

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000514

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00321

GnomAD4 exome

AF:

0.00371

AC:

5326

AN:

1434242

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

2598

AN XY:

714630

show subpopulations

African (AFR)

AF:

0.000693

AC:

AN:

33190

American (AMR)

AF:

0.00197

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00737

AC:

192

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.000302

AC:

AN:

85970

European-Finnish (FIN)

AF:

0.000639

AC:

AN:

39120

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00435

AC:

4782

AN:

1100104

Other (OTH)

AF:

0.00294

AC:

176

AN:

59842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

251

502

752

1003

1254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.00238

AC:

362

AN:

152286

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

156

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41550

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00390

AC:

265

AN:

68012

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00356

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000803

AC:

ESP6500EA

AF:

0.00402

AC:

ExAC

AF:

0.00245

AC:

291

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Inborn genetic diseases (1)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.0

(source)

DANN

Benign

0.43

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.46

M_CAP

Benign

0.023

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.98

PhyloP100

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.41

REVEL

Benign

0.099

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.14

MVP

0.11

MPC

0.021

ClinPred

0.0066

GERP RS

0.40

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(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