chr12-80217643-T-C

Position:

chr12-80217643-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378609.3(OTOGL):c.214T>C(p.Trp72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,552,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.50

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1269213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.214T>C	p.Trp72Arg	missense_variant	5/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
OTOGL	ENST00000547103.7 linkuse as main transcript	c.214T>C	p.Trp72Arg	missense_variant	5/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1 linkuse as main transcript	c.214T>C	p.Trp72Arg	missense_variant	10/63
OTOGL	ENST00000643417.1 linkuse as main transcript	n.874T>C		non_coding_transcript_exon_variant	8/23

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

191844

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

103512

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000129

AC:

AN:

1400716

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

695102

show subpopulations

Gnomad4 AFR exome

AF:

0.000335

Gnomad4 AMR exome

AF:

0.000123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000341

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000277

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 31, 2016

The p.Trp63Arg variant in OTOGL has not been previously reported in individuals with hearing loss, and has been identified in 1/1188 Latino chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs36947 3810). Although this variant has been seen in the general population, its frequ ency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Trp63Arg v ariant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.187T>C (p.W63R) alteration is located in exon 4 (coding exon 4) of the OTOGL gene. This alteration results from a T to C substitution at nucleotide position 187, causing the tryptophan (W) at amino acid position 63 to be replaced by an arginine (R). 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

-0.22

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.39

T;.;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

.;.;N

REVEL

Benign

0.18

Sift

Benign

0.088

.;.;T

Sift4G

Benign

0.34

.;.;T

Vest4

0.61

MutPred

0.67

.;.;Gain of disorder (P = 0.0186);

MVP

0.25

MPC

0.029

ClinPred

0.027

GERP RS

3.4

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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