rs143890524

Variant names:

• chr16-21736341-G-A
• rs143890524
• NM_144672.4:c.2382G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-21736341-G-A
• chr16-21736341-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_144672.4(OTOA):​c.2382G>A​(p.Gln794Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,567,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (0 hom.)
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.135
• Publications: 9 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 -11 ACMG points.

• PM2: Variant has high frequency in the EAS (0.166) population. However there is too low homozygotes in high coverage region: (expected more than 16, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-21736341-G-A is Benign according to our data. Variant chr16-21736341-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 506082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.135 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.2382G>A	p.Gln794Gln	synonymous_variant	Exon 22 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.2382G>A	p.Gln794Gln	synonymous_variant	Exon 22 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2436 AN: 148178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.00554

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.0222

GnomAD2 exomes AF: 0.00223 AC: 506 AN: 227182 AF XY: 0.00194

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.00230

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00554 AC: 7861 AN: 1418908 Hom.: 0 Cov.: 32 AF XY: 0.00524 AC XY: 3704 AN XY: 706408

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

African (AFR) AF: 0.000420 AC: 14 AN: 33328

American (AMR) AF: 0.0507 AC: 1660 AN: 32772

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 48 AN: 25644

East Asian (EAS) AF: 0.170 AC: 4359 AN: 25602

South Asian (SAS) AF: 0.00252 AC: 209 AN: 82902

European-Finnish (FIN) AF: 0.0129 AC: 625 AN: 48314

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5678

European-Non Finnish (NFE) AF: 0.000493 AC: 546 AN: 1107004

Other (OTH) AF: 0.00678 AC: 391 AN: 57664

⚠️ 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: 0.0165 AC: 2445 AN: 148288 Hom.: 0 Cov.: 32 AF XY: 0.0193 AC XY: 1395 AN XY: 72128

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

African (AFR) AF: 0.00305 AC: 126 AN: 41344

American (AMR) AF: 0.0597 AC: 835 AN: 13982

Ashkenazi Jewish (ASJ) AF: 0.00554 AC: 19 AN: 3428

East Asian (EAS) AF: 0.180 AC: 726 AN: 4024

South Asian (SAS) AF: 0.0198 AC: 92 AN: 4650

European-Finnish (FIN) AF: 0.0447 AC: 442 AN: 9898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00224 AC: 152 AN: 67714

Other (OTH) AF: 0.0259 AC: 53 AN: 2044

⚠️ 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: 0.00717 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln794Gln in exon 21 of OTOA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 21.59% (1708/7910) o f East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs143890524). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.093
DANN	Benign	0.35
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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: rs143890524; hg19: chr16-21747662; COSMIC: COSV53748438;