16-21736318-G-T

Variant names:

• chr16-21736318-G-T
• rs200988634
• NM_144672.4:c.2359G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_144672.4(OTOA):​c.2359G>T​(p.Glu787*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0035 in 1,567,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
• Consequence: OTOA NM_144672.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 5.04
• Publications: 26 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, 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Variant has high frequency in the EAS (0.113) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).
• PP5: Variant 16-21736318-G-T is Pathogenic according to our data. Variant chr16-21736318-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218841.

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.2359G>T	p.Glu787*	stop_gained	Exon 22 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.2122G>T	p.Glu708*	stop_gained	Exon 17 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.1387G>T	p.Glu463*	stop_gained	Exon 12 of 19	NP_733764.1	Q7RTW8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.2359G>T	p.Glu787*	stop_gained	Exon 22 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.2359G>T	p.Glu787*	stop_gained	Exon 21 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.2401G>T	p.Glu801*	stop_gained	Exon 21 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1513 AN: 146726 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.00176

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0126

GnomAD2 exomes AF: 0.000308 AC: 75 AN: 243820 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00248

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00279 AC: 3962 AN: 1420162 Hom.: 0 Cov.: 32 AF XY: 0.00270 AC XY: 1907 AN XY: 707040

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

African (AFR) AF: 0.000180 AC: 6 AN: 33354

American (AMR) AF: 0.0146 AC: 502 AN: 34434

Ashkenazi Jewish (ASJ) AF: 0.000506 AC: 13 AN: 25672

East Asian (EAS) AF: 0.116 AC: 2798 AN: 24096

South Asian (SAS) AF: 0.000349 AC: 29 AN: 83132

European-Finnish (FIN) AF: 0.00574 AC: 277 AN: 48246

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5680

European-Non Finnish (NFE) AF: 0.000163 AC: 180 AN: 1107680

Other (OTH) AF: 0.00268 AC: 155 AN: 57868

⚠️ 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: 0.0104 AC: 1525 AN: 146842 Hom.: 0 Cov.: 32 AF XY: 0.0118 AC XY: 844 AN XY: 71254

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

African (AFR) AF: 0.00194 AC: 80 AN: 41260

American (AMR) AF: 0.0392 AC: 529 AN: 13498

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 6 AN: 3404

East Asian (EAS) AF: 0.126 AC: 460 AN: 3642

South Asian (SAS) AF: 0.0118 AC: 54 AN: 4588

European-Finnish (FIN) AF: 0.0277 AC: 266 AN: 9612

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

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67630

Other (OTH) AF: 0.0155 AC: 31 AN: 2004

⚠️ 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: 0.00886 Hom.: 0

ExAC AF: 0.00175 AC: 212

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	-	Autosomal recessive nonsyndromic hearing loss 22 (6)
-	2	-	not specified (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		5.0
Vest4		0.26
GERP RS		4.2
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200988634; hg19: chr16-21747639; COSMIC: COSV53748571;