16-21678558-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144672.4(OTOA):c.44T>G(p.Phe15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F15Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2858285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOA	NM_144672.4	c.44T>G	p.Phe15Cys	missense_variant	2/29	ENST00000646100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2	c.44T>G	p.Phe15Cys	missense_variant	2/29		NM_144672.4	P2
OTOA	ENST00000388958.8	c.44T>G	p.Phe15Cys	missense_variant	1/28	1		P2
OTOA	ENST00000286149.8	c.44T>G	p.Phe15Cys	missense_variant	1/28	5		A2
OTOA	ENST00000647277.1	c.44T>G	p.Phe15Cys	missense_variant, NMD_transcript_variant	2/29

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	0.067
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.51	T
Vest4		0.62, 0.64
MutPred		0.36		Gain of catalytic residue at L16 (P = 0.0159);Gain of catalytic residue at L16 (P = 0.0159);Gain of catalytic residue at L16 (P = 0.0159);
MVP		0.82
MPC		0.77
ClinPred		0.84	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs78970023; hg19: chr16-21689879;