16-21722967-G-C

Variant names:

• chr16-21722967-G-C
• NM_144672.4:c.1869G>C
• OTOA p.Leu623Phe

Variant summary

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

The NM_144672.4(OTOA):​c.1869G>C​(p.Leu623Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOA NM_144672.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• 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: G2P, Laboratory for Molecular Medicine, 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 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.1869G>C	p.Leu623Phe	missense	Exon 18 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.1632G>C	p.Leu544Phe	missense	Exon 13 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.897G>C	p.Leu299Phe	missense	Exon 8 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.1869G>C	p.Leu623Phe	missense	Exon 18 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.1869G>C	p.Leu623Phe	missense	Exon 17 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.1911G>C	p.Leu637Phe	missense	Exon 17 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.50
Sift	Benign	0.066	T
Sift4G	Benign	0.098	T
Varity_R		0.11
gMVP		0.53

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-21734288;