rs72640475

chr16-21730867-G-Achr16-21730867-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_144672.4(OTOA):c.2238G>A(p.Thr746=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 146,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.017 (421 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.08

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 -16 ACMG points.

• BP6: Variant 16-21730867-G-A is Benign according to our data. Variant chr16-21730867-G-A is described in ClinVar as [Benign]. Clinvar id is 47953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.2238G>A	p.Thr746=	synonymous_variant	21/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.2238G>A	p.Thr746=	synonymous_variant	21/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2126 AN: 146584 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.00443

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00239

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0533 AC: 12804 AN: 240440 Hom.: 346 AF XY: 0.0454 AC XY: 5897 AN XY: 129832

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.234

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.0755

Gnomad NFE exome AF: 0.00625

Gnomad OTH exome AF: 0.0352

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0165 AC: 23282 AN: 1410698 Hom.: 421 Cov.: 29 AF XY: 0.0159 AC XY: 11157 AN XY: 702380

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.00847

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.0568

Gnomad4 NFE exome AF: 0.00230

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0146 AC: 2136 AN: 146692 Hom.: 0 Cov.: 31 AF XY: 0.0175 AC XY: 1249 AN XY: 71226

Gnomad4 AFR AF: 0.00182

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.00443

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.00239

Gnomad4 OTH AF: 0.0225

Alfa AF: 0.00802 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Thr746Thr in Exon 20 of OTOA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.3% (22/6966) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs76494517). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 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. -

Autosomal recessive nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.22
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -30

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

Publications

LitVar

Other links and lift over

dbSNP: rs72640475; hg19: chr16-21742188; COSMIC: COSV53752929;