16-21678407-CATAT-C

Variant names:

• chr16-21678407-CATAT-C
• rs113757042
• NM_144672.4:c.-4-93_-4-90delATAT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144672.4(OTOA):​c.-4-93_-4-90delATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000999 in 500,312 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: OTOA NM_144672.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.872
• Publications: 1 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	NM_144672.4	MANE Select	c.-4-93_-4-90delATAT		intron	N/A	NP_653273.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.-4-103_-4-100delATAT		intron	N/A	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000647277.1		n.-4-103_-4-100delATAT		intron	N/A	ENSP00000495594.1	A0A2R8YG28
	OTOA	ENST00000388958.8	TSL:1	c.-107_-104delATAT		upstream_gene	N/A	ENSP00000373610.3	Q7RTW8-5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000999 AC: 5 AN: 500312 Hom.: 0 AF XY: 0.0000189 AC XY: 5 AN XY: 264036

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

African (AFR) AF: 0.00 AC: 0 AN: 10436

American (AMR) AF: 0.0000673 AC: 1 AN: 14854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14362

East Asian (EAS) AF: 0.00 AC: 0 AN: 20338

South Asian (SAS) AF: 0.00 AC: 0 AN: 37030

European-Finnish (FIN) AF: 0.0000314 AC: 1 AN: 31830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1864

European-Non Finnish (NFE) AF: 0.00000580 AC: 2 AN: 344692

Other (OTH) AF: 0.0000402 AC: 1 AN: 24906

⚠️ 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 Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87

Splicing

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

Other links and lift over

dbSNP: rs113757042; hg19: chr16-21689728;