rs727503351

Variant names:

• chr16-21722978-C-G
• rs727503351
• NM_144672.4:c.1880C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-21722978-C-G
• chr16-21722978-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_144672.4(OTOA):​c.1880C>G​(p.Pro627Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P627S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OTOA NM_144672.4 missense, splice_region
• Scores: Splicing: ADA: 0.5697
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.26
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-21722977-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100655.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 16-21722978-C-G is Pathogenic according to our data. Variant chr16-21722978-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164825.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4	c.1880C>G	p.Pro627Arg	missense_variant, splice_region_variant	Exon 18 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2	c.1880C>G	p.Pro627Arg	missense_variant, splice_region_variant	Exon 18 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461680 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

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: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111828

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

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 627 of the OTOA protein (p.Pro627Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive deafness (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 164825). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Pro627 amino acid residue in OTOA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23173898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Nov 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro627Arg variant in OTOA has not been previously reported in individuals with hearing loss or in large population studies. Another variant at this positi on (p.Pro627Ser) has been reported in 2 Pakistani individuals with non-syndromic hearing loss, and segregated with disease in 2 affected siblings from 2 familie s (Lee 2013), suggesting that changes that this position may affect the protein. Computational prediction tools and conservation analyses suggest that the p.Pro 627Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located at the last nucleotide of the exon, which is part of the 5' splice region. Computation al tools do not suggest an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the p.Pro627Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	.;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	.;D;.;.;D
Vest4		0.92, 0.93, 0.92, 0.86
MutPred		0.53		.;Loss of loop (P = 9e-04);.;.;.;
MVP		0.88
MPC		0.66
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.61
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.43
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

Other links and lift over

dbSNP: rs727503351; hg19: chr16-21734299;