16-21736318-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144672.4(OTOA):​c.2359G>C​(p.Glu787Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27657777).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	NM_144672.4	MANE Select	c.2359G>C	p.Glu787Gln	missense	Exon 22 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.2122G>C	p.Glu708Gln	missense	Exon 17 of 24	NP_001155155.1
	OTOA	NM_170664.3		c.1387G>C	p.Glu463Gln	missense	Exon 12 of 19	NP_733764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOA	ENST00000646100.2	MANE Select	c.2359G>C	p.Glu787Gln	missense	Exon 22 of 29	ENSP00000496564.2
	OTOA	ENST00000388958.8	TSL:1	c.2359G>C	p.Glu787Gln	missense	Exon 21 of 28	ENSP00000373610.3
	OTOA	ENST00000286149.8	TSL:5	c.2401G>C	p.Glu801Gln	missense	Exon 21 of 28	ENSP00000286149.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457784 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725420

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 43398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 38674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111352

Other (OTH) AF: 0.00 AC: 0 AN: 60074

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.32		Gain of MoRF binding (P = 0.0211)
MVP		0.76
MPC		0.63
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;