Variant 2-240139346-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_148961.4(OTOS):c.94G>A(p.Ala32Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,612,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

OTOS
NM_148961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

Variant links:

Genes affected

OTOS (HGNC:22644): (otospiralin) Otospiralin is synthesized by nonsensory cells (fibrocytes) of the inner ear, and downregulation of otospiralin in guinea pigs leads to deafness (Lavigne-Rebillard et al., 2003 [PubMed 12687421]).[supplied by OMIM, Mar 2008]

OTOS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024873108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OTOS	NM_148961.4 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	4/4	ENST00000319460.2	NP_683764.1
OTOS	XM_017003409.2 linkuse as main transcript	c.151G>A	p.Ala51Thr	missense_variant	4/4		XP_016858898.1
OTOS	XM_017003410.2 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	4/4		XP_016858899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOS	ENST00000319460.2 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	4/4	5	NM_148961.4	ENSP00000322486	P1
OTOS	ENST00000391989.6 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	5/5	3		ENSP00000375849	P1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

248198

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

134390

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000186

AC:

271

AN:

1460340

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

726340

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000197

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.94G>A (p.A32T) alteration is located in exon 4 (coding exon 3) of the OTOS gene. This alteration results from a G to A substitution at nucleotide position 94, causing the alanine (A) at amino acid position 32 to be replaced by a threonine (T). 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

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.58

.;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.022

Sift

Benign

0.56

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.012

B;B

Vest4

0.084

MVP

0.18

MPC

0.040

ClinPred

0.035

GERP RS

1.8

Varity_R

0.042

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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