16-21722977-C-T

Position:

• chr16-21722977-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_144672.4(OTOA):​c.1879C>T​(p.Pro627Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: OTOA NM_144672.4 missense, splice_region
• Scores: Splicing: ADA: 0.9592
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.26

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-21722977-C-T is Pathogenic according to our data. Variant chr16-21722977-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100655.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr16-21722977-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOA	NM_144672.4	c.1879C>T	p.Pro627Ser	missense_variant, splice_region_variant	18/29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.1879C>T	p.Pro627Ser	missense_variant, splice_region_variant	18/29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251298 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 22 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	The OTOA c.1879C>T (p.Pro627Ser) is a missens mutation and results at the protein level is a disfunctional or truncated protein, predicted lead to disease.This variant is not present in Iranian population databases. This variant as Pathogenic according to the ACMG classification. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 627 of the OTOA protein (p.Pro627Ser). This variant is present in population databases (rs587777133, gnomAD 0.03%). This missense change has been observed in individuals with deafness (PMID: 23173898). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 100655). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23173898, 24963352, 31527525) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	.;D;D;D;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.020	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	.;D;.;.;D
Vest4		0.93, 0.87, 0.85, 0.71
MutPred		0.48		.;Gain of helix (P = 0.062);.;.;.;
MVP		0.85
MPC		0.69
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.88
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: rs587777133; hg19: chr16-21734298;