chr16-21697781-CTGCTT-A

Position:

• chr16-21697781-CTGCTT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144672.4(OTOA):​c.746_751delinsA​(p.Ser249TyrfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOA NM_144672.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-21697781-CTGCTT-A is Pathogenic according to our data. Variant chr16-21697781-CTGCTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOA	NM_144672.4	c.746_751delinsA	p.Ser249TyrfsTer21	frameshift_variant	10/29	ENST00000646100.2	NP_653273.3
OTOA	NM_001161683.2	c.509_514delinsA	p.Ser170TyrfsTer21	frameshift_variant	5/24		NP_001155155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.746_751delinsA	p.Ser249TyrfsTer21	frameshift_variant	10/29		NM_144672.4	ENSP00000496564	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2023

Frameshift variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2015

The p.Ser249fs variant in OTOA has not been previously reported in individuals w ith hearing loss. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 249 and leads to a prema ture termination codon 21 amino acids downstream. This alteration is then predic ted to lead to a truncated or absent protein. Loss of function of the OTOA gene is an established disease mechanism in autosomal recessive sensorineural hearing loss. In summary, this variant meets our criteria to be classified as pathogeni c for hearing loss in an autosomal recessive manner (www.partners.org/personaliz edmedicine/lmm), based on the predicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657716; hg19: chr16-21709102;