rs568139514

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_144672.4(OTOA):c.3377T>C(p.Leu1126Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 150,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.089012384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
OTOA	NM_144672.4 linkuse as main transcript	c.3377T>C	p.Leu1126Pro	missense_variant	29/29	ENST00000646100.2
OTOA	NM_001161683.2 linkuse as main transcript	c.3140T>C	p.Leu1047Pro	missense_variant	24/24
OTOA	NM_170664.3 linkuse as main transcript	c.2405T>C	p.Leu802Pro	missense_variant	19/19
OTOA	XM_011545748.3 linkuse as main transcript	c.2246T>C	p.Leu749Pro	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2 linkuse as main transcript	c.3377T>C	p.Leu1126Pro	missense_variant	29/29		NM_144672.4	P2	Q7RTW8-5

Frequencies

GnomAD3 genomes

AF:

0.000193

AC:

AN:

150466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000425

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000355

Gnomad OTH

AF:

0.000490

GnomAD3 exomes

AF:

0.000245

AC:

AN:

249268

Hom.:

AF XY:

0.000282

AC XY:

AN XY:

134864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000245

AC:

356

AN:

1454618

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

180

AN XY:

723760

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.000193

AC:

AN:

150588

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000425

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000355

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.000330

Hom.:

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

The Leu1126Pro variant in OTOA has been previously identified in two individuals with hearing loss by our laboratory, however neither patient carried a second O TOA variant and one individual had pathogenic variants in another gene that expl ained the hearing loss. Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support f or or against an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.3377T>C (p.L1126P) alteration is located in exon 28 (coding exon 28) of the OTOA gene. This alteration results from a T to C substitution at nucleotide position 3377, causing the leucine (L) at amino acid position 1126 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hearing impairment

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, BP4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.67

M_CAP

Benign

0.030

MetaRNN

Benign

0.089

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.42

Polyphen

0.92, 0.96

.;P;.;.;D

Vest4

0.84, 0.77, 0.76, 0.60

MVP

0.70

MPC

4.3

ClinPred

0.074

GERP RS

2.5

Varity_R

0.55

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over