NM_144672.4:c.1522G>C

Variant names:

• chr16-21716940-G-C
• rs150415498
• NM_144672.4:c.1522G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144672.4(OTOA):​c.1522G>C​(p.Val508Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. V508A) has been classified as Likely benign.

• 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: 0.370
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046762228).

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.1522G>C	p.Val508Leu	missense	Exon 15 of 29	NP_653273.3
	OTOA	NM_001161683.2		c.1285G>C	p.Val429Leu	missense	Exon 10 of 24	NP_001155155.1	Q7RTW8-4
	OTOA	NM_170664.3		c.550G>C	p.Val184Leu	missense	Exon 5 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.1522G>C	p.Val508Leu	missense	Exon 15 of 29	ENSP00000496564.2	Q7RTW8-5
	OTOA	ENST00000388958.8	TSL:1	c.1522G>C	p.Val508Leu	missense	Exon 14 of 28	ENSP00000373610.3	Q7RTW8-5
	OTOA	ENST00000286149.8	TSL:5	c.1564G>C	p.Val522Leu	missense	Exon 14 of 28	ENSP00000286149.4	Q7RTW8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.6
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.37
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.057
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Polyphen		0.072	B
Vest4		0.099
MutPred		0.27		Gain of helix (P = 0.2059)
MVP		0.49
MPC		0.17
ClinPred		0.050	T
GERP RS		1.8
Varity_R		0.053
gMVP		0.078
Mutation Taster		=99/1	polymorphism

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: rs150415498; hg19: chr16-21728261;