chr12-80355852-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378609.3(OTOGL):c.5710G>A(p.Asp1904Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,898 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1904E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 51 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.29

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009504139).

BP6

Variant 12-80355852-G-A is Benign according to our data. Variant chr12-80355852-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80355852-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00571 (869/152258) while in subpopulation NFE AF= 0.00487 (331/68020). AF 95% confidence interval is 0.00443. There are 13 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.5710G>A	p.Asp1904Asn	missense_variant	Exon 47 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOGL	ENST00000547103.7 link	c.5710G>A	p.Asp1904Asn	missense_variant	Exon 47 of 59	5	NM_001378609.3	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1 link	c.5575G>A	p.Asp1859Asn	missense_variant	Exon 51 of 63			ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7 link	c.1009G>A	p.Asp337Asn	missense_variant	Exon 8 of 18	5		ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.00571

AC:

869

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00487

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00568

AC:

1401

AN:

246510

Hom.:

AF XY:

0.00535

AC XY:

717

AN XY:

133932

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0388

Gnomad NFE exome

AF:

0.00364

Gnomad OTH exome

AF:

0.00548

GnomAD4 exome

AF:

0.00325

AC:

4756

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

2359

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.00371

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0376

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00321

GnomAD4 genome

AF:

0.00571

AC:

869

AN:

152258

Hom.:

Cov.:

AF XY:

0.00747

AC XY:

556

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.00487

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00362

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00241

AC:

ExAC

AF:

0.00499

AC:

603

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOGL: BP4 -

not specified

Benign:2

Jun 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp1895Asn in exon 46 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 3.79% (251/6614) of Finnish chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs145653077). -

Jan 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;.;T

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.8

.;D;N

REVEL

Benign

0.10

Sift

Benign

0.12

.;T;T

Sift4G

Benign

0.55

.;.;T

Vest4

0.30

MVP

0.22

MPC

0.041

ClinPred

0.035

GERP RS

4.3

gMVP

0.28

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