NM_001378609.3:c.1815G>T

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.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. 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.1815G>T	p.Gln605His	missense_variant	Exon 18 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOGL	ENST00000547103.7 link	c.1815G>T	p.Gln605His	missense_variant	Exon 18 of 59	5	NM_001378609.3	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1 link	c.1815G>T	p.Gln605His	missense_variant	Exon 23 of 63			ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000643417.1 link	n.2475G>T		non_coding_transcript_exon_variant	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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as heterozygous in a patient with neonatal onset encephalopathy, brain atrophy with cerebellar malformation, and later-onset seizures who was also heterozygous for the Q1216H variant; however, this patient harbored a homozygous nonsense variant in the TBCK gene which the authors concluded was likely the causative variant (Chong et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27040692) -

not specified

Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The OTOGL p.Gln596His variant was identified in dbSNP (ID: rs192234924) and ClinVar (classified as likely benign by Invitae and Laboratory for Molecular Medicine) but was not identified in LOVD 3.0. The variant was identified in the literature in a family with TBCK-associated infantile syndromic encephalopathy; the OTOGL variant was not expected to contribute to the phenotype (Chong_2016_PMID:27040692). The variant was identified in control databases in 92 of 264632 chromosomes (2 homozygous) at a frequency of 0.0003477 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 78 of 23824 chromosomes (freq: 0.003274) and Latino in 14 of 34894 chromosomes (freq: 0.000401), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Gln596 residue is conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Jul 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln596His in exon 17 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (79/23656) of African chromos omes, including 2 homozygotes individual by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org; dbSNP rs192234924). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

T;.;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.88

PhyloP100

1.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.4

.;.;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

.;.;D

Sift4G

Uncertain

0.0030

.;.;D

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over