rs16972658

Positions:

• chr16-21687628-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.615C>T​(p.Arg205Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,611,076 control chromosomes in the GnomAD database, including 1,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (105 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1101 hom.)
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.63

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=-0.75).
• BP6: Variant 16-21687628-C-T is Benign according to our data. Variant chr16-21687628-C-T is described in ClinVar as [Benign]. Clinvar id is 47955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOA	NM_144672.4	c.615C>T	p.Arg205Arg	synonymous_variant	8/29	ENST00000646100.2	NP_653273.3
OTOA	NM_001161683.2	c.378C>T	p.Arg126Arg	synonymous_variant	3/24		NP_001155155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.615C>T	p.Arg205Arg	synonymous_variant	8/29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5100 AN: 150456 Hom.: 105 Cov.: 31

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00157

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0439

GnomAD3 exomes AF: 0.0305 AC: 7640 AN: 250478 Hom.: 147 AF XY: 0.0310 AC XY: 4200 AN XY: 135480

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0354 AC: 51649 AN: 1460578 Hom.: 1101 Cov.: 34 AF XY: 0.0349 AC XY: 25375 AN XY: 726592

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.0279

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.00807

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0355

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0367

GnomAD4 genome AF: 0.0339 AC: 5104 AN: 150498 Hom.: 105 Cov.: 31 AF XY: 0.0346 AC XY: 2542 AN XY: 73384

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.00157

Gnomad4 SAS AF: 0.0103

Gnomad4 FIN AF: 0.0367

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0388 Hom.: 151

Bravo AF: 0.0335

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0465

EpiControl AF: 0.0475

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg205Arg in Exon 07 of OTOA: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 3.7% (263/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs16972658). -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.20
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs16972658; hg19: chr16-21698949; COSMIC: COSV53751991;