NM_144672.4:c.44T>A

Variant names:

• chr16-21678558-T-A
• rs78970023
• NM_144672.4:c.44T>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:5
• Conservation: PhyloP100: 2.42
• Publications: 23 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.44T>A	p.Phe15Tyr	missense_variant	Exon 2 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.44T>A	p.Phe15Tyr	missense_variant	Exon 2 of 29		NM_144672.4	ENSP00000496564.2
OTOA	ENST00000388958.8	c.44T>A	p.Phe15Tyr	missense_variant	Exon 1 of 28	1		ENSP00000373610.3
OTOA	ENST00000286149.8	c.44T>A	p.Phe15Tyr	missense_variant	Exon 1 of 28	5		ENSP00000286149.4
OTOA	ENST00000647277.1	n.44T>A		non_coding_transcript_exon_variant	Exon 2 of 29			ENSP00000495594.1

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

GnomAD2 exomes AF: 0.0681 AC: 17125 AN: 251456 AF XY: 0.0585

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 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

African (AFR) AF: 0.0787 AC: 2632 AN: 33458

American (AMR) AF: 0.214 AC: 9582 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 788 AN: 26126

East Asian (EAS) AF: 0.322 AC: 12734 AN: 39596

South Asian (SAS) AF: 0.0396 AC: 3417 AN: 86248

European-Finnish (FIN) AF: 0.0137 AC: 734 AN: 53406

Middle Eastern (MID) AF: 0.0486 AC: 280 AN: 5766

European-Non Finnish (NFE) AF: 0.00866 AC: 9629 AN: 1111908

Other (OTH) AF: 0.0348 AC: 2101 AN: 60384

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

African (AFR) AF: 0.0808 AC: 3351 AN: 41450

American (AMR) AF: 0.120 AC: 1825 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 114 AN: 3472

East Asian (EAS) AF: 0.265 AC: 1363 AN: 5150

South Asian (SAS) AF: 0.0502 AC: 242 AN: 4818

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00948 AC: 645 AN: 68012

Other (OTH) AF: 0.0551 AC: 116 AN: 2104

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.023	.;T;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.46	.;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;M
PhyloP100		2.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.67	.;N;N
REVEL	Benign	0.17
Sift	Benign	0.030	.;D;D
Sift4G	Uncertain	0.042	.;D;D
Vest4		0.12, 0.17
MPC		0.47
ClinPred		0.021	T
GERP RS		4.7
PromoterAI		-0.013	Neutral
Varity_R		0.084
gMVP		0.11
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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