16-21736318-G-T

Variant names:

• chr16-21736318-G-T
• rs200988634
• NM_144672.4:c.2359G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_144672.4(OTOA):​c.2359G>T​(p.Glu787*) 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:6 U:3
• Conservation: PhyloP100: 5.04
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 22

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Variant has high frequency in the EAS (0.113) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).
• 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 VariationId is 218841.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	NM_144672.4	MANE Select	c.2359G>T	p.Glu787*	stop_gained	Exon 22 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.2122G>T	p.Glu708*	stop_gained	Exon 17 of 24	NP_001155155.1
	OTOA	NM_170664.3		c.1387G>T	p.Glu463*	stop_gained	Exon 12 of 19	NP_733764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.2359G>T	p.Glu787*	stop_gained	Exon 22 of 29	ENSP00000496564.2
	OTOA	ENST00000388958.8	TSL:1	c.2359G>T	p.Glu787*	stop_gained	Exon 21 of 28	ENSP00000373610.3
	OTOA	ENST00000286149.8	TSL:5	c.2401G>T	p.Glu801*	stop_gained	Exon 21 of 28	ENSP00000286149.4

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

GnomAD2 exomes AF: 0.000308 AC: 75 AN: 243820 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00248

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000168

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000180 AC: 6 AN: 33354

American (AMR) AF: 0.0146 AC: 502 AN: 34434

Ashkenazi Jewish (ASJ) AF: 0.000506 AC: 13 AN: 25672

East Asian (EAS) AF: 0.116 AC: 2798 AN: 24096

South Asian (SAS) AF: 0.000349 AC: 29 AN: 83132

European-Finnish (FIN) AF: 0.00574 AC: 277 AN: 48246

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5680

European-Non Finnish (NFE) AF: 0.000163 AC: 180 AN: 1107680

Other (OTH) AF: 0.00268 AC: 155 AN: 57868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00194 AC: 80 AN: 41260

American (AMR) AF: 0.0392 AC: 529 AN: 13498

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 6 AN: 3404

East Asian (EAS) AF: 0.126 AC: 460 AN: 3642

South Asian (SAS) AF: 0.0118 AC: 54 AN: 4588

European-Finnish (FIN) AF: 0.0277 AC: 266 AN: 9612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67630

Other (OTH) AF: 0.0155 AC: 31 AN: 2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00886 Hom.: 0

ExAC AF: 0.00175 AC: 212

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 22 Pathogenic:5 Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 25, 2021

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 28, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not specified Uncertain:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare genetic deafness Pathogenic:1

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		5.0
Vest4		0.26
GERP RS		4.2
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

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