rs183159689

Variant names:

Variant summary

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

The NM_001378609.3(OTOGL):c.2564C>T(p.Pro855Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,613,152 control chromosomes in the GnomAD database, including 5 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 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 5 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.73

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01609394).

BP6

Variant 12-80271693-C-T is Benign according to our data. Variant chr12-80271693-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229115.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00103 (157/152198) while in subpopulation AMR AF = 0.00288 (44/15280). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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	UniProt
OTOGL	NM_001378609.3	MANE Select	c.2564C>T	p.Pro855Leu	missense	Exon 24 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.2564C>T	p.Pro855Leu	missense	Exon 27 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.2564C>T	p.Pro855Leu	missense	Exon 24 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.2564C>T	p.Pro855Leu	missense	Exon 24 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.2564C>T	p.Pro855Leu	missense	Exon 29 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000752

AC:

185

AN:

246064

AF XY:

0.000696

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00181

Gnomad ASJ exome

AF:

0.000797

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000735

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.000570

AC:

833

AN:

1460954

Hom.:

Cov.:

AF XY:

0.000572

AC XY:

416

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33428

American (AMR)

AF:

0.00200

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00573

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000501

AC:

557

AN:

1111456

Other (OTH)

AF:

0.00166

AC:

100

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00103

AC:

157

AN:

152198

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41534

American (AMR)

AF:

0.00288

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000740

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00102

AC:

ESP6500EA

AF:

0.000363

AC:

ExAC

AF:

0.000605

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hearing impairment (1)

not specified (1)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

M_CAP

Benign

0.020

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.2

PhyloP100

2.7

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.15

Sift

Benign

0.35

Sift4G

Uncertain

0.040

Vest4

0.55

MVP

0.18

MPC

0.18

ClinPred

0.039

GERP RS

5.1

gMVP

0.49

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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