Variant 2-240140280-C-A 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.47G>T(p.Gly16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,595,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

OTOS
NM_148961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.352

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=0.016695648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOS	NM_148961.4 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	2/4	ENST00000319460.2	NP_683764.1	Q8NHW6
OTOS	XM_017003409.2 linkuse as main transcript	c.104G>T	p.Gly35Val	missense_variant	2/4		XP_016858898.1
OTOS	XM_017003410.2 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	2/4		XP_016858899.1	Q8NHW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOS	ENST00000319460.2 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	2/4	5	NM_148961.4	ENSP00000322486.1		Q8NHW6
OTOS	ENST00000391989.6 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	3/5	3		ENSP00000375849.2		Q8NHW6

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000967

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:

0.0000879

AC:

AN:

216182

Hom.:

AF XY:

0.0000597

AC XY:

AN XY:

117170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1443668

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

716526

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000566

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000970

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.000116

AC:

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

May 03, 2023

The c.47G>T (p.G16V) alteration is located in exon 2 (coding exon 1) of the OTOS gene. This alteration results from a G to T substitution at nucleotide position 47, causing the glycine (G) at amino acid position 16 to be replaced by a valine (V). 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

0.073

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.16

Sift

Benign

0.51

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.028

B;B

Vest4

0.21

MVP

0.50

MPC

0.039

ClinPred

0.047

GERP RS

1.9

Varity_R

0.18

gMVP

0.51

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