rs138141474

Positions:

• chr16-21716941-T-C

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.1523T>C​(p.Val508Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,614,072 control chromosomes in the GnomAD database, including 3 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. V508M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -0.843

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=0.0050311983).
• BP6: Variant 16-21716941-T-C is Benign according to our data. Variant chr16-21716941-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21716941-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.1523T>C	p.Val508Ala	missense_variant	15/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.1523T>C	p.Val508Ala	missense_variant	15/29		NM_144672.4	P2

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 251322 Hom.: 1 AF XY: 0.00105 AC XY: 142 AN XY: 135816

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000753 AC: 1101 AN: 1461850 Hom.: 1 Cov.: 32 AF XY: 0.000762 AC XY: 554 AN XY: 727232

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000480

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74444

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00128 Hom.: 2

Bravo AF: 0.00114

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Autosomal recessive nonsyndromic hearing loss 22 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Nov 03, 2015

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2017

p.Val508Ala in exon 14 of OTOA: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote 8 mammals have an alanine (Ala) at this position despite high nearby amino a cid conservation. In addition, computational analyses do not suggest a high like lihood of impact to the protein. This variant has been identified in 1% (110/101 40) of Ashkenazi Jewish chromosomes including 1 homozygote by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138141474). -

OTOA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 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	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.96
DANN	Benign	0.44
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0050	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
Polyphen		0.0010, 0.0030	.;B;.;.;B
Vest4		0.078, 0.068, 0.062, 0.083
MVP		0.47
MPC		0.20
ClinPred		0.0012	T
GERP RS		1.8
Varity_R		0.032
gMVP		0.063

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: rs138141474; hg19: chr16-21728262;