dbSNP rs186616540: OTOGL:p.Gly310Glu (chr12-80238962-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.929G>A(p.Gly310Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00492 in 1,597,246 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 34 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.28

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=0.0076597035).

BP6

Variant 12-80238962-G-A is Benign according to our data. Variant chr12-80238962-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226978.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 = 0.00309 (471/152228) while in subpopulation NFE AF = 0.00513 (349/67996). AF 95% confidence interval is 0.00469. There are 3 homozygotes in GnomAd4. There are 229 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.929G>A	p.Gly310Glu	missense	Exon 10 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.929G>A	p.Gly310Glu	missense	Exon 13 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.929G>A	p.Gly310Glu	missense	Exon 10 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.929G>A	p.Gly310Glu	missense	Exon 10 of 59	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.929G>A	p.Gly310Glu	missense	Exon 15 of 63	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000643417.1		n.1589G>A		non_coding_transcript_exon	Exon 13 of 23

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

472

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00515

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00268

AC:

621

AN:

231836

AF XY:

0.00261

show subpopulations

Gnomad AFR exome

AF:

0.000998

Gnomad AMR exome

AF:

0.000709

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00363

Gnomad NFE exome

AF:

0.00478

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00512

AC:

7393

AN:

1445018

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

3522

AN XY:

719058

show subpopulations

African (AFR)

AF:

0.000808

AC:

AN:

33412

American (AMR)

AF:

0.000971

AC:

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.000268

AC:

AN:

85692

European-Finnish (FIN)

AF:

0.00399

AC:

156

AN:

39050

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00624

AC:

6932

AN:

1110936

Other (OTH)

AF:

0.00332

AC:

200

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

379

759

1138

1518

1897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.00309

AC:

471

AN:

152228

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41532

American (AMR)

AF:

0.00222

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00513

AC:

349

AN:

67996

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00410

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.00303

AC:

ExAC

AF:

0.00252

AC:

300

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.65

Eigen

Benign

0.087

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.56

M_CAP

Benign

0.020

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.97

PhyloP100

4.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.21

REVEL

Benign

0.064

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.26

MVP

0.13

MPC

0.027

ClinPred

0.013

GERP RS

4.3

gMVP

0.38

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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