rs78970023

chr16-21678558-T-Achr16-21678558-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144672.4(OTOA):c.44T>A(p.Phe15Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,613,658 control chromosomes in the GnomAD database, including 4,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (492 hom., cov: 31)
  • Exomes 𝑓: 0.029 (3839 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003518194).
• BP6: Variant 16-21678558-T-A is Benign according to our data. Variant chr16-21678558-T-A is described in ClinVar as [Benign]. Clinvar id is 47954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.44T>A	p.Phe15Tyr	missense_variant	2/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.44T>A	p.Phe15Tyr	missense_variant	2/29		NM_144672.4	P2
OTOA	ENST00000388958.8	c.44T>A	p.Phe15Tyr	missense_variant	1/28	1		P2
OTOA	ENST00000286149.8	c.44T>A	p.Phe15Tyr	missense_variant	1/28	5		A2
OTOA	ENST00000647277.1	c.44T>A	p.Phe15Tyr	missense_variant, NMD_transcript_variant	2/29

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7760 AN: 151944 Hom.: 485 Cov.: 31

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00950

Gnomad OTH AF: 0.0567

GnomAD3 exomes AF: 0.0681 AC: 17125 AN: 251456 Hom.: 1808 AF XY: 0.0585 AC XY: 7951 AN XY: 135912

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.0412

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0287 AC: 41897 AN: 1461596 Hom.: 3839 Cov.: 32 AF XY: 0.0281 AC XY: 20448 AN XY: 727124

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.0396

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00866

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0512 AC: 7785 AN: 152062 Hom.: 492 Cov.: 31 AF XY: 0.0537 AC XY: 3992 AN XY: 74350

Gnomad4 AFR AF: 0.0808

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0328

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.0502

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.00948

Gnomad4 OTH AF: 0.0551

Alfa AF: 0.0253 Hom.: 226

Bravo AF: 0.0658

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.0780 AC: 343

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.0623 AC: 7569

Asia WGS AF: 0.132 AC: 456 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Phe15Tyr in Exon 01 of OTOA: This variant is not expected to have clinical signi ficance because it has been identified in 8.2% (305/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs78970023). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.51	T
Vest4		0.12, 0.17
MPC		0.47
ClinPred		0.021	T
GERP RS		4.7
Varity_R		0.084
gMVP		0.11

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: rs78970023; hg19: chr16-21689879; COSMIC: COSV53761154;