NM_001378609.3:c.1990C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378609.3(OTOGL):c.1990C>T(p.Pro664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,610,908 control chromosomes in the GnomAD database, including 17 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 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 17 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 7.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011739701).

BP6

Variant 12-80262069-C-T is Benign according to our data. Variant chr12-80262069-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr12-80262069-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00159 (242/152142) while in subpopulation SAS AF= 0.00686 (33/4814). AF 95% confidence interval is 0.00502. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.1990C>T	p.Pro664Ser	missense_variant	Exon 19 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOGL	ENST00000547103.7 link	c.1990C>T	p.Pro664Ser	missense_variant	Exon 19 of 59	5	NM_001378609.3	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1 link	c.1990C>T	p.Pro664Ser	missense_variant	Exon 24 of 63			ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000643417.1 link	n.2650C>T		non_coding_transcript_exon_variant	Exon 22 of 23

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00706

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00248

AC:

609

AN:

245976

Hom.:

AF XY:

0.00295

AC XY:

394

AN XY:

133684

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.000797

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00885

Gnomad FIN exome

AF:

0.000929

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.00233

GnomAD4 exome

AF:

0.00193

AC:

2810

AN:

1458766

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1657

AN XY:

725640

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00852

Gnomad4 FIN exome

AF:

0.000938

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152142

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00686

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00207

AC:

ExAC

AF:

0.00266

AC:

321

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOGL: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Aug 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro655Ser in exon 18 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.9% (149/16498) of South Asian ch romosomes including 2 homozygotes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs76420383). -

Inborn genetic diseases

Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1963C>T (p.P655S) alteration is located in exon 18 (coding exon 18) of the OTOGL gene. This alteration results from a C to T substitution at nucleotide position 1963, causing the proline (P) at amino acid position 655 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;.;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.3

.;.;D

REVEL

Benign

0.23

Sift

Uncertain

0.0050

.;.;D

Sift4G

Pathogenic

0.0

.;.;D

Vest4

0.80

MVP

0.29

MPC

0.19

ClinPred

0.039

GERP RS

5.6

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over