rs80356569

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2317C>T(p.Arg773Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,602,582 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 32)

Exomes 𝑓: 0.014 ( 227 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Splicing: ADA: 0.8316

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 7.79

Publications

10 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=0.0074848533).

BP6

Variant 2-26477505-G-A is Benign according to our data. Variant chr2-26477505-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	Exon 3 of 29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2377

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0154

AC:

3504

AN:

227648

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0518

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0139

AC:

20232

AN:

1450336

Hom.:

227

Cov.:

AF XY:

0.0144

AC XY:

10352

AN XY:

720362

show subpopulations

African (AFR)

AF:

0.0216

AC:

719

AN:

33364

American (AMR)

AF:

0.0150

AC:

650

AN:

43212

Ashkenazi Jewish (ASJ)

AF:

0.0541

AC:

1401

AN:

25876

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39340

South Asian (SAS)

AF:

0.0230

AC:

1945

AN:

84456

European-Finnish (FIN)

AF:

0.000782

AC:

AN:

51130

Middle Eastern (MID)

AF:

0.0551

AC:

316

AN:

5740

European-Non Finnish (NFE)

AF:

0.0127

AC:

14064

AN:

1107290

Other (OTH)

AF:

0.0183

AC:

1095

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1182

2364

3546

4728

5910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.0156

AC:

2377

AN:

152246

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1140

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0217

AC:

901

AN:

41552

American (AMR)

AF:

0.0167

AC:

255

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0203

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

875

AN:

68010

Other (OTH)

AF:

0.0303

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

123

246

370

493

616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0153

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.0210

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.0145

AC:

1746

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Aug 05, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22607986, 12114484, 16371502, 19461658) -

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

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 20, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

.;.;.;T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T;T

MetaRNN

Benign

0.0075

T;T;T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.3

.;.;.;M;M;.

PhyloP100

7.8

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

D;D;.;D;D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.014

D;D;.;D;D;.

Sift4G

Uncertain

0.031

D;D;.;D;D;.

Polyphen

0.17

B;D;.;D;.;D

Vest4

0.73

MPC

0.49

ClinPred

0.029

GERP RS

4.7

Varity_R

0.21

gMVP

0.45

Mutation Taster

=54/46

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Pathogenic

0.78

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over