rs461179

chr16-21730858-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144672.4(OTOA):c.2229C>T(p.Ala743=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 141,714 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1123 hom., cov: 30)
  • Exomes 𝑓: 0.030 (5452 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.31

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-21730858-C-T is Benign according to our data. Variant chr16-21730858-C-T is described in ClinVar as [Benign]. Clinvar id is 164827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21730858-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.2229C>T	p.Ala743=	synonymous_variant	21/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.2229C>T	p.Ala743=	synonymous_variant	21/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 14999 AN: 141612 Hom.: 1116 Cov.: 30

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0738

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0305 AC: 7072 AN: 232152 Hom.: 1293 AF XY: 0.0293 AC XY: 3689 AN XY: 125858

Gnomad AFR exome AF: 0.00931

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0932

Gnomad SAS exome AF: 0.0477

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0295 AC: 39417 AN: 1334280 Hom.: 5452 Cov.: 29 AF XY: 0.0322 AC XY: 21326 AN XY: 661458

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0414

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0881

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.0415

GnomAD4 genome AF: 0.106 AC: 15010 AN: 141714 Hom.: 1123 Cov.: 30 AF XY: 0.110 AC XY: 7556 AN XY: 68698

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.110

Alfa AF: 0.115 Hom.: 278

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2015	p.Ala743Ala in Exon 20 of OTOA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence and it has been identified in 0.4% (490/11461 0) of chromosomes including 62 individuals who were homozygous by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; rs139312489). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.070
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs461179; hg19: chr16-21742179; COSMIC: COSV53748363;