rs2141652614

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144672.4(OTOA):c.86G>A(p.Arg29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,276 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. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.164

Publications

0 publications found

Variant links:

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

OTOA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.090437025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4 link	c.86G>A	p.Arg29Lys	missense_variant	Exon 2 of 29	ENST00000646100.2	NP_653273.3	Q05BM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOA	ENST00000646100.2 link	c.86G>A	p.Arg29Lys	missense_variant	Exon 2 of 29		NM_144672.4	ENSP00000496564.2	Q7RTW8-5
OTOA	ENST00000388958.8 link	c.86G>A	p.Arg29Lys	missense_variant	Exon 1 of 28	1		ENSP00000373610.3	Q7RTW8-5
OTOA	ENST00000286149.8 link	c.86G>A	p.Arg29Lys	missense_variant	Exon 1 of 28	5		ENSP00000286149.4	Q7RTW8-1
OTOA	ENST00000647277.1 link	n.86G>A		non_coding_transcript_exon_variant	Exon 2 of 29			ENSP00000495594.1	A0A2R8YG28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111502

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.86G>A (p.R29K) alteration is located in exon 1 (coding exon 1) of the OTOA gene. This alteration results from a G to A substitution at nucleotide position 86, causing the arginine (R) at amino acid position 29 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 03, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.0

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0090

.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.43

.;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

0.16

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.22

.;N;N

REVEL

Benign

0.049

Sift

Benign

0.35

.;T;T

Sift4G

Benign

0.99

.;T;T

Vest4

0.15, 0.14

MutPred

0.28

Gain of ubiquitination at R29 (P = 0.0104);Gain of ubiquitination at R29 (P = 0.0104);Gain of ubiquitination at R29 (P = 0.0104);

MVP

0.67

MPC

0.17

ClinPred

0.097

GERP RS

1.2

PromoterAI

0.015

Neutral

(source)

Varity_R

0.047

gMVP

0.26

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over