dbSNP rs770892393: OTOA:c.268-2A>G (chr16-21685228-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_144672.4(OTOA):c.268-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,459,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OTOA
NM_144672.4 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.38

Variant links:

Genes affected

OTOA (HGNC:16378): (otoancorin) The protein encoded by this gene is specifically expressed in the inner ear, and is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. It is prposed that this protein is involved in the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. Mutations in this gene are associated with autosomal recessive deafness type 22 (DFNB22). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OTOA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038596492 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-21685228-A-G is Pathogenic according to our data. Variant chr16-21685228-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 505849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4 link	c.268-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 28	ENST00000646100.2	NP_653273.3	Q05BM7
OTOA	NM_001161683.2 link	c.31-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 23		NP_001155155.1	Q7RTW8-4Q05BM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2 link	c.268-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 28		NM_144672.4	ENSP00000496564.2		Q7RTW8-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251104

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459142

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rare genetic deafness

Pathogenic:1

May 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268-2A>G variant in OTOA has not been previously reported in individuals w ith hearing loss, but has been identified in 1/111514 European chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s770892393). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Th is variant occurs in the invariant region (+/- 1/2) of the splice consensus sequ ence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the OTOA gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the pr edicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Benign

0.92

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Benign

0.24

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.87

Position offset: 6

DS_AL_spliceai

1.0

Position offset: 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