rs200988634

chr16-21736318-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 9P and 8B. PVS1 PP5 BA1

The NM_144672.4(OTOA):c.2359G>T(p.Glu787Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0035 in 1,567,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
• Consequence: OTOA NM_144672.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-21736318-G-T is Pathogenic according to our data. Variant chr16-21736318-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218841.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=3, Likely_pathogenic=1}. Variant chr16-21736318-G-T is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.2359G>T	p.Glu787Ter	stop_gained	22/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.2359G>T	p.Glu787Ter	stop_gained	22/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1513 AN: 146726 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.00176

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0126

GnomAD4 exome AF: 0.00279 AC: 3962 AN: 1420162 Hom.: 0 Cov.: 32 AF XY: 0.00270 AC XY: 1907 AN XY: 707040

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.000506

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.000349

Gnomad4 FIN exome AF: 0.00574

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.0104 AC: 1525 AN: 146842 Hom.: 0 Cov.: 32 AF XY: 0.0118 AC XY: 844 AN XY: 71254

Gnomad4 AFR AF: 0.00194

Gnomad4 AMR AF: 0.0392

Gnomad4 ASJ AF: 0.00176

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.0155

Alfa AF: 0.00886 Hom.: 0

ExAC AF: 0.00175 AC: 212

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 22 Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.E787* in OTOA (NM_144672.4) has been previously reported in affected individuals (Lindor et al, 2015). The variant is present in OTOP which overlaps with a pseudogene and hence currently without confirmation via long rage PCR and sanger it is not possible to predict if the variant arises from the gene or pseudogene. The variant is present in gnomAD database but has been flagged as having low sequencing quality and may not represent true frequency. The variant has been submitted to ClinVar as Likey Pathogenic/ Uncertain significance. If confirmed to be present in the gene OTOA, it is predicted to cause protein truncation. Loss of function variants have been previousy reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2023	Variant summary: OTOA c.2359G>T (p.Glu787X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00031 in 243820 control chromosomes (gnomAD). c.2359G>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss or unilateral auditory neuropathy (van Beeck Calkoen_2019, Song_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34175691, 31152317). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2022

The c.2359G>T, p.Glu787X variant in OTOA is a nonsense variant leads to a premature termination codon at position 787, which is predicted to lead to a truncated or absent protein. Of note, the OTOA gene has a pseudogene (OTOAP1, loc653786) that contains this nucleotide variant as the reference base (GrCH37 chr16:22563762) in humans. As such, the p.Glu787X variant requires long range PCR to determine whether the variant exists in the OTOA or OTOAP1 gene. This variant has been identified in 1 individual by our laboratory who harbored a deletion of the OTOA gene on the remaining allele, and the p.Glu787X variant was confirmed by long range PCR in both the proband and an unaffected parent. Furthermore, the variant has been previously reported in 2 individual with hearing loss who carried a second pathogenic variang in OTOA, and in the heterozygous state in 1 healthy individual (Gao 2013 PMID: 23690975, Lindor 2015 PMID: 26434960, Laurent 2021 PMID: 33492714); one of the studies performed long range PCR to confirm the presence of the variant in the gene. This variant has also been reported in 1% (165/16068) of East Asian chromosomes by gnomAD; however, it failed the sequencing quality metric filter in this database and thus contamination from the pseudogene cannot be ruled out for those individuals (http://gnomad.broadinstitute.org). As such, the population frequency of this variant is unknown. Loss of function of the OTOA gene is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss, provided that it is confirmed to be present in the OTOA gene and not the OTOAP1 pseudogene. ACMG/AMP Criteria applied: PVS1, PM3_S. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.26, 0.26, 0.27
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs200988634; hg19: chr16-21747639; COSMIC: COSV53748571;