rs13031859

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_194248.3(OTOF):c.244C>T(p.Arg82Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,595,874 control chromosomes in the GnomAD database, including 166,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 11813 hom., cov: 33)

Exomes 𝑓: 0.45 ( 154466 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.50

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.0906329E-4).

BP6

Variant 2-26519093-G-A is Benign according to our data. Variant chr2-26519093-G-A is described in ClinVar as Benign. ClinVar VariationId is 21836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.244C>T	p.Arg82Cys	missense_variant	Exon 4 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.244C>T	p.Arg82Cys	missense_variant	Exon 4 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.244C>T	p.Arg82Cys	missense_variant	Exon 4 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.244C>T	p.Arg82Cys	missense_variant	Exon 4 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.359

AC:

54604

AN:

152024

Hom.:

11810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.485

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.0815

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.428

GnomAD2 exomes

AF:

0.404

AC:

93598

AN:

231612

AF XY:

0.412

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.497

Gnomad ASJ exome

AF:

0.454

Gnomad EAS exome

AF:

0.0898

Gnomad FIN exome

AF:

0.345

Gnomad NFE exome

AF:

0.474

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.453

AC:

653833

AN:

1443732

Hom.:

154466

Cov.:

AF XY:

0.452

AC XY:

324413

AN XY:

717318

show subpopulations

African (AFR)

AF:

0.129

AC:

4290

AN:

33348

American (AMR)

AF:

0.494

AC:

21523

AN:

43530

Ashkenazi Jewish (ASJ)

AF:

0.456

AC:

11700

AN:

25668

East Asian (EAS)

AF:

0.0905

AC:

3579

AN:

39530

South Asian (SAS)

AF:

0.403

AC:

34082

AN:

84628

European-Finnish (FIN)

AF:

0.351

AC:

18416

AN:

52410

Middle Eastern (MID)

AF:

0.513

AC:

2944

AN:

5740

European-Non Finnish (NFE)

AF:

0.484

AC:

531527

AN:

1099210

Other (OTH)

AF:

0.432

AC:

25772

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

18164

36328

54492

72656

90820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15496

30992

46488

61984

77480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.359

AC:

54617

AN:

152142

Hom.:

11813

Cov.:

AF XY:

0.355

AC XY:

26385

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.137

AC:

5697

AN:

41524

American (AMR)

AF:

0.485

AC:

7415

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1579

AN:

3470

East Asian (EAS)

AF:

0.0815

AC:

422

AN:

5180

South Asian (SAS)

AF:

0.379

AC:

1827

AN:

4822

European-Finnish (FIN)

AF:

0.348

AC:

3683

AN:

10590

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.479

AC:

32570

AN:

67952

Other (OTH)

AF:

0.426

AC:

900

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1608

3217

4825

6434

8042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.438

Hom.:

25275

Bravo

AF:

0.362

TwinsUK

AF:

0.498

AC:

1846

ALSPAC

AF:

0.503

AC:

1938

ESP6500AA

AF:

0.139

AC:

614

ESP6500EA

AF:

0.485

AC:

4171

ExAC

AF:

0.382

AC:

46128

Asia WGS

AF:

0.225

AC:

787

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 07, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg82Cys variant in OTOF is classified as benign because it has been identified in 40% (104,089/262,952) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

May 09, 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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:3Other:1

May 28, 2019

Mendelics

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

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.058

T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.00021

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.5

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.37

N;N

REVEL

Benign

0.060

Sift

Benign

0.075

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0020

B;.

Vest4

0.34

MPC

0.21

ClinPred

0.021

GERP RS

1.2

Varity_R

0.079

gMVP

0.48

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over