rs1879761

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_194248.3(OTOF):c.158C>T(p.Ala53Val) variant causes a missense change. The variant allele was found at a frequency of 0.0227 in 1,613,822 control chromosomes in the GnomAD database, including 4,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 529 hom., cov: 32)

Exomes 𝑓: 0.022 ( 4160 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017544031).

BP6

Variant 2-26527901-G-A is Benign according to our data. Variant chr2-26527901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26527901-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.158C>T	p.Ala53Val	missense_variant	Exon 3 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.158C>T	p.Ala53Val	missense_variant	Exon 3 of 46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.158C>T	p.Ala53Val	missense_variant	Exon 3 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.158C>T	p.Ala53Val	missense_variant	Exon 3 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4884

AN:

152066

Hom.:

524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00279

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0655

AC:

16470

AN:

251374

Hom.:

2310

AF XY:

0.0548

AC XY:

7448

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.278

Gnomad SAS exome

AF:

0.0197

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.00289

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0218

AC:

31808

AN:

1461638

Hom.:

4160

Cov.:

AF XY:

0.0206

AC XY:

14987

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.268

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.322

Gnomad4 SAS exome

AF:

0.0204

Gnomad4 FIN exome

AF:

0.0150

Gnomad4 NFE exome

AF:

0.00240

Gnomad4 OTH exome

AF:

0.0280

GnomAD4 genome

AF:

0.0322

AC:

4894

AN:

152184

Hom.:

529

Cov.:

AF XY:

0.0372

AC XY:

2771

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00513

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.291

Gnomad4 SAS

AF:

0.0234

Gnomad4 FIN

AF:

0.0177

Gnomad4 NFE

AF:

0.00279

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.0140

Hom.:

400

Bravo

AF:

0.0460

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.0537

AC:

6520

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala53Val in exon 3 of OTOF: This variant is not expected to have clinical signif icance because it was detected in normal hearing controls and it involves a chan ge at a position that is not conserved (Jiminez 2007, Varga 2006). In addition, it has been seen in an unpublished study with a minor allele frequency of 3% and has been identified in 10/122 (8%) of individuals tested by our laboratory. Thi s variant is also listed in dbSNP (rs1879761 - no frequency data available). -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:2Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

0.094

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.11

Sift

Benign

0.15

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.18

B;.

Vest4

0.47

MPC

0.22

ClinPred

0.0084

GERP RS

4.5

Varity_R

0.18

gMVP

0.48

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