Genetic Variant OTOGL:p.Ile2095Val (chr12-80366589-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001378609.3(OTOGL):c.6283A>G(p.Ile2095Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,404,176 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 26)

Exomes 𝑓: 0.00063 ( 4 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.545

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008036017).

BP6

Variant 12-80366589-A-G is Benign according to our data. Variant chr12-80366589-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (259/148198) while in subpopulation AFR AF = 0.00391 (160/40882). AF 95% confidence interval is 0.00342. There are 1 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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.6283A>G	p.Ile2095Val	missense	Exon 53 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.6283A>G	p.Ile2095Val	missense	Exon 56 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.6283A>G	p.Ile2095Val	missense	Exon 53 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.6283A>G	p.Ile2095Val	missense	Exon 53 of 59	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.6148A>G	p.Ile2050Val	missense	Exon 57 of 63	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7	TSL:5	c.1526-972A>G		intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

259

AN:

148174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00272

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00662

Gnomad NFE

AF:

0.000713

Gnomad OTH

AF:

0.00440

GnomAD2 exomes

AF:

0.000905

AC:

157

AN:

173430

AF XY:

0.000842

show subpopulations

Gnomad AFR exome

AF:

0.00389

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.000734

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000727

Gnomad OTH exome

AF:

0.00253

GnomAD4 exome

AF:

0.000631

AC:

792

AN:

1255978

Hom.:

Cov.:

AF XY:

0.000623

AC XY:

387

AN XY:

621326

show subpopulations

African (AFR)

AF:

0.00448

AC:

125

AN:

27884

American (AMR)

AF:

0.00218

AC:

AN:

31254

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

21222

East Asian (EAS)

AF:

0.00

AC:

AN:

31318

South Asian (SAS)

AF:

0.0000372

AC:

AN:

53724

European-Finnish (FIN)

AF:

0.0000673

AC:

AN:

29710

Middle Eastern (MID)

AF:

0.00688

AC:

AN:

5084

European-Non Finnish (NFE)

AF:

0.000447

AC:

449

AN:

1004890

Other (OTH)

AF:

0.00200

AC:

102

AN:

50892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

104

130

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:

0.00175

AC:

259

AN:

148198

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

117

AN XY:

72100

show subpopulations

African (AFR)

AF:

0.00391

AC:

160

AN:

40882

American (AMR)

AF:

0.00265

AC:

AN:

14742

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

4994

South Asian (SAS)

AF:

0.00

AC:

AN:

4672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8920

Middle Eastern (MID)

AF:

0.00719

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000713

AC:

AN:

67288

Other (OTH)

AF:

0.00437

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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:

0.00114

Hom.:

Bravo

AF:

0.00212

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000923

AC:

110

Asia WGS

AF:

0.00146

AC:

AN:

3446

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.40

M_CAP

Benign

0.0030

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.0

PhyloP100

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.67

REVEL

Benign

0.026

Sift

Benign

0.31

Sift4G

Benign

0.33

Vest4

0.13

MVP

0.030

MPC

0.021

ClinPred

0.0013

GERP RS

-1.6

gMVP

0.45

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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