rs461179

Variant names:

• chr16-21730858-C-T
• rs461179
• NM_144672.4:c.2229C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_144672.4(OTOA):​c.2229C>T​(p.Ala743Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 141,714 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1123 hom., cov: 30)
  • Exomes 𝑓: 0.030 (5452 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.31
• Publications: 6 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-21730858-C-T is Benign according to our data. Variant chr16-21730858-C-T is described in ClinVar as Benign. ClinVar VariationId is 164827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 1123 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.2229C>T	p.Ala743Ala	synonymous_variant	Exon 21 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.2229C>T	p.Ala743Ala	synonymous_variant	Exon 21 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 14999 AN: 141612 Hom.: 1116 Cov.: 30

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0738

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0305 AC: 7072 AN: 232152 AF XY: 0.0293

Gnomad AFR exome AF: 0.00931

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0932

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0295 AC: 39417 AN: 1334280 Hom.: 5452 Cov.: 29 AF XY: 0.0322 AC XY: 21326 AN XY: 661458

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0100 AC: 328 AN: 32716

American (AMR) AF: 0.0414 AC: 1664 AN: 40218

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1457 AN: 22926

East Asian (EAS) AF: 0.111 AC: 3516 AN: 31668

South Asian (SAS) AF: 0.0881 AC: 6114 AN: 69382

European-Finnish (FIN) AF: 0.0702 AC: 3232 AN: 46072

Middle Eastern (MID) AF: 0.0438 AC: 224 AN: 5116

European-Non Finnish (NFE) AF: 0.0200 AC: 20628 AN: 1031850

Other (OTH) AF: 0.0415 AC: 2254 AN: 54332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.106 AC: 15010 AN: 141714 Hom.: 1123 Cov.: 30 AF XY: 0.110 AC XY: 7556 AN XY: 68698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0351 AC: 1425 AN: 40550

American (AMR) AF: 0.128 AC: 1786 AN: 13926

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 548 AN: 3184

East Asian (EAS) AF: 0.231 AC: 1013 AN: 4380

South Asian (SAS) AF: 0.220 AC: 918 AN: 4170

European-Finnish (FIN) AF: 0.158 AC: 1431 AN: 9082

Middle Eastern (MID) AF: 0.147 AC: 38 AN: 258

European-Non Finnish (NFE) AF: 0.120 AC: 7570 AN: 63312

Other (OTH) AF: 0.110 AC: 215 AN: 1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.115 Hom.: 278

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala743Ala in Exon 20 of OTOA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence and it has been identified in 0.4% (490/11461 0) of chromosomes including 62 individuals who were homozygous by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; rs139312489). -

Feb 29, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2018

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. -

not provided Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 22 Benign:1

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.070
DANN	Benign	0.76
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs461179; hg19: chr16-21742179; COSMIC: COSV53748363;