rs150415498

chr16-21716940-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144672.4(OTOA):c.1522G>A(p.Val508Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,006 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.370

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005751699).
• BP6: Variant 16-21716940-G-A is Benign according to our data. Variant chr16-21716940-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.1522G>A	p.Val508Met	missense_variant	15/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.1522G>A	p.Val508Met	missense_variant	15/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00586

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00218 AC: 547 AN: 251320 Hom.: 2 AF XY: 0.00218 AC XY: 296 AN XY: 135812

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00540

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00220 AC: 3218 AN: 1461850 Hom.: 11 Cov.: 32 AF XY: 0.00220 AC XY: 1599 AN XY: 727234

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00558

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152156 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74378

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00586

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00282 Hom.: 2

Bravo AF: 0.00141

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00245

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	OTOA: BP4 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 13, 2017

p.Val508Met in exon 14 of OTOA: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (150/25792) of Finnish and 0.3 3% (423/126554) European chromosomes including 3 homozygotes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs150415498). -

OTOA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Benign	0.95
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.037	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
Polyphen		0.18, 0.32	.;B;.;.;B
Vest4		0.13, 0.13, 0.12, 0.092
MVP		0.50
MPC		0.18
ClinPred		0.0044	T
GERP RS		1.8
Varity_R		0.041
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150415498; hg19: chr16-21728261;