NM_144672.4:c.1322T>C

Variant names:

• chr16-21714986-T-C
• rs1555499893
• NM_144672.4:c.1322T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144672.4(OTOA):​c.1322T>C​(p.Val441Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOA NM_144672.4 missense, splice_region
• Scores: Splicing: ADA: 0.01411
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20370063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.1322T>C	p.Val441Ala	missense_variant, splice_region_variant	Exon 14 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.1322T>C	p.Val441Ala	missense_variant, splice_region_variant	Exon 14 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

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

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

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

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Val441Ala var iant in OTOA has not been previously reported in individuals with hearing loss, or in large population studies. Valine (Val) at position 441 is not conserved in mammals or evolutionarily distant species. Of note, 2 mammals (chinchilla and s tar-nosed mole) carry an alanine (Ala) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools su pport that the variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In summary, while the clinical si gnificance of the p.Val441Ala variant is uncertain, these data suggest that it i s more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	.;T;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	.;T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	.;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.046	.;D;T;T;T
Sift4G	Uncertain	0.0060	.;D;D;D;D
Polyphen		1.0, 0.66	.;D;.;.;P
Vest4		0.18, 0.18, 0.21, 0.17
MutPred		0.33		.;Loss of methylation at K454 (P = 0.0426);.;.;.;
MVP		0.70
MPC		0.23
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.070		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: rs1555499893; hg19: chr16-21726307;