rs72640475

Variant names:

• chr16-21730867-G-A
• rs72640475
• NM_144672.4:c.2238G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-21730867-G-A
• chr16-21730867-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_144672.4(OTOA):​c.2238G>A​(p.Thr746Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 146,692 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.017 (421 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOA NM_144672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.08
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Variant has high frequency in the EAS (0.161) population. However there is too low homozygotes in high coverage region: (expected more than 7, got 0).
• BP6: Variant 16-21730867-G-A is Benign according to our data. Variant chr16-21730867-G-A is described in ClinVar as Benign. ClinVar VariationId is 47953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.2238G>A	p.Thr746Thr	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.2238G>A	p.Thr746Thr	synonymous_variant	Exon 21 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2126 AN: 146584 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.00443

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00239

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0533 AC: 12804 AN: 240440 AF XY: 0.0454

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.0755

Gnomad NFE exome AF: 0.00625

Gnomad OTH exome AF: 0.0352

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0165 AC: 23282 AN: 1410698 Hom.: 421 Cov.: 29 AF XY: 0.0159 AC XY: 11157 AN XY: 702380

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

African (AFR) AF: 0.00180 AC: 60 AN: 33260

American (AMR) AF: 0.163 AC: 6576 AN: 40386

Ashkenazi Jewish (ASJ) AF: 0.00847 AC: 213 AN: 25144

East Asian (EAS) AF: 0.250 AC: 7969 AN: 31840

South Asian (SAS) AF: 0.0200 AC: 1633 AN: 81838

European-Finnish (FIN) AF: 0.0568 AC: 2938 AN: 51708

Middle Eastern (MID) AF: 0.00819 AC: 45 AN: 5492

European-Non Finnish (NFE) AF: 0.00230 AC: 2494 AN: 1083286

Other (OTH) AF: 0.0234 AC: 1354 AN: 57744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0146 AC: 2136 AN: 146692 Hom.: 0 Cov.: 31 AF XY: 0.0175 AC XY: 1249 AN XY: 71226

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

African (AFR) AF: 0.00182 AC: 75 AN: 41134

American (AMR) AF: 0.0460 AC: 623 AN: 13538

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 15 AN: 3384

East Asian (EAS) AF: 0.171 AC: 679 AN: 3966

South Asian (SAS) AF: 0.0187 AC: 83 AN: 4440

European-Finnish (FIN) AF: 0.0465 AC: 455 AN: 9782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00239 AC: 161 AN: 67250

Other (OTH) AF: 0.0225 AC: 45 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0114 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 13, 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. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr746Thr in Exon 20 of OTOA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.3% (22/6966) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs76494517). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 22 Benign:1

Aug 29, 2018

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	-0.90
CADD	Benign	0.22
DANN	Benign	0.78
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72640475; hg19: chr16-21742188; COSMIC: COSV53752929;