dbSNP rs143817729: OTOGL:p.Glu1636Lys (chr12-80339120-G-A) – 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.4906G>A(p.Glu1636Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00204 in 1,611,698 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.22

Publications

6 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=0.00897333).

BP6

Variant 12-80339120-G-A is Benign according to our data. Variant chr12-80339120-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227824.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 = 0.00135 (205/151878) while in subpopulation NFE AF = 0.00218 (148/67830). AF 95% confidence interval is 0.00189. There are 3 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.4906G>A	p.Glu1636Lys	missense	Exon 43 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.4906G>A	p.Glu1636Lys	missense	Exon 46 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.4906G>A	p.Glu1636Lys	missense	Exon 43 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.4906G>A	p.Glu1636Lys	missense	Exon 43 of 59	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.4771G>A	p.Glu1591Lys	missense	Exon 47 of 63	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7	TSL:5	c.205G>A	p.Glu69Lys	missense	Exon 4 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

206

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00165

AC:

407

AN:

246378

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00588

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00226

Gnomad OTH exome

AF:

0.00415

GnomAD4 exome

AF:

0.00211

AC:

3075

AN:

1459820

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1506

AN XY:

726298

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33420

American (AMR)

AF:

0.00208

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00582

AC:

152

AN:

26102

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00238

AC:

2644

AN:

1110284

Other (OTH)

AF:

0.00245

AC:

148

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00135

AC:

205

AN:

151878

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41472

American (AMR)

AF:

0.00131

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00491

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00218

AC:

148

AN:

67830

Other (OTH)

AF:

0.000952

AC:

AN:

2100

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:

0.00199

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00135

AC:

ExAC

AF:

0.00166

AC:

200

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

M_CAP

Benign

0.011

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.95

PhyloP100

4.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.97

REVEL

Benign

0.091

Sift

Benign

0.12

Sift4G

Benign

0.092

Vest4

0.22

MVP

0.38

MPC

0.027

ClinPred

0.018

GERP RS

5.7

gMVP

0.59

Mutation Taster

=98/2

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