Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378609.3(OTOGL):c.1990C>T(p.Pro664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,610,908 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 17 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 7.42

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011739701).

BP6

Variant 12-80262069-C-T is Benign according to our data. Variant chr12-80262069-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226931.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00159 (242/152142) while in subpopulation SAS AF = 0.00686 (33/4814). AF 95% confidence interval is 0.00502. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

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	HGVSp	Effect	Exon Rank	Protein
OTOGL	NM_001378609.3	MANE Select	c.1990C>T	p.Pro664Ser	missense	Exon 19 of 59	NP_001365538.2
OTOGL	NM_001378610.3		c.1990C>T	p.Pro664Ser	missense	Exon 22 of 62	NP_001365539.2
OTOGL	NM_173591.7		c.1990C>T	p.Pro664Ser	missense	Exon 19 of 59	NP_775862.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.1990C>T	p.Pro664Ser	missense	Exon 19 of 59	ENSP00000447211.2
OTOGL	ENST00000646859.1		c.1990C>T	p.Pro664Ser	missense	Exon 24 of 63	ENSP00000496036.1
OTOGL	ENST00000643417.1		n.2650C>T		non_coding_transcript_exon	Exon 22 of 23

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00706

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00248

AC:

609

AN:

245976

AF XY:

0.00295

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.000797

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.000929

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.00233

GnomAD4 exome

AF:

0.00193

AC:

2810

AN:

1458766

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1657

AN XY:

725640

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33394

American (AMR)

AF:

0.00121

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26066

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39580

South Asian (SAS)

AF:

0.00852

AC:

731

AN:

85794

European-Finnish (FIN)

AF:

0.000938

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00156

AC:

1727

AN:

1110132

Other (OTH)

AF:

0.00237

AC:

143

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

132

263

395

526

658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00159

AC:

242

AN:

152142

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41530

American (AMR)

AF:

0.00177

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00686

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00204

AC:

139

AN:

67986

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00191

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00207

AC:

ExAC

AF:

0.00266

AC:

321

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

PhyloP100

7.4

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.3

REVEL

Benign

0.23

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Vest4

0.80

MVP

0.29

MPC

0.19

ClinPred

0.039

GERP RS

5.6

gMVP

0.74

Mutation Taster

=67/33

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

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

rs76420383

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