Genetic Variant OTOGL:p.Gln605His (chr12-80257928-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_001378609.3(OTOGL):c.1815G>T(p.Gln605His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,598,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00092 ( 2 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.09

Publications

0 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=0.02024138).

BP6

Variant 12-80257928-G-T is Benign according to our data. Variant chr12-80257928-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227812.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00092 (140/152198) while in subpopulation AFR AF = 0.0026 (108/41532). AF 95% confidence interval is 0.0022. There are 2 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.1815G>T	p.Gln605His	missense	Exon 18 of 59	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.1815G>T	p.Gln605His	missense	Exon 21 of 62	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.1815G>T	p.Gln605His	missense	Exon 18 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.1815G>T	p.Gln605His	missense	Exon 18 of 59	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.1815G>T	p.Gln605His	missense	Exon 23 of 63	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000643417.1		n.2475G>T		non_coding_transcript_exon	Exon 21 of 23

Frequencies

GnomAD3 genomes

AF:

0.000921

AC:

140

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000266

AC:

AN:

233246

AF XY:

0.000188

show subpopulations

Gnomad AFR exome

AF:

0.00318

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000754

AC:

109

AN:

1445988

Hom.:

Cov.:

AF XY:

0.0000792

AC XY:

AN XY:

719676

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33412

American (AMR)

AF:

0.000337

AC:

AN:

44474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111204

Other (OTH)

AF:

0.000216

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000920

AC:

140

AN:

152198

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41532

American (AMR)

AF:

0.00203

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

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:

0.000297

Hom.:

Bravo

AF:

0.00113

ESP6500AA

AF:

0.00298

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000320

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.59

M_CAP

Benign

0.071

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.88

PhyloP100

1.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.4

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Vest4

0.71

MutPred

0.71

Loss of stability (P = 0.0866)

MVP

0.34

MPC

0.18

ClinPred

0.077

GERP RS

3.7

gMVP

0.66

Mutation Taster

=93/7

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