rs17005371

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.4936C>T(p.Pro1646Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0343 in 1,600,522 control chromosomes in the GnomAD database, including 8,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1646T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.14 ( 4306 hom., cov: 32)

Exomes 𝑓: 0.023 ( 3929 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 6.62

Publications

19 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=0.0014489889).

BP6

Variant 2-26464893-G-A is Benign according to our data. Variant chr2-26464893-G-A is described in ClinVar as Benign. ClinVar VariationId is 21856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.4936C>T	p.Pro1646Ser	missense_variant	Exon 39 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 link	c.2635C>T	p.Pro879Ser	missense_variant	Exon 22 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.4936C>T	p.Pro1646Ser	missense_variant	Exon 39 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8 link	c.2635C>T	p.Pro879Ser	missense_variant	Exon 22 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20919

AN:

151994

Hom.:

4284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0682

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.0437

AC:

10621

AN:

243164

AF XY:

0.0363

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.0286

Gnomad ASJ exome

AF:

0.0457

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000371

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0234

AC:

33854

AN:

1448410

Hom.:

3929

Cov.:

AF XY:

0.0225

AC XY:

16163

AN XY:

719826

show subpopulations

African (AFR)

AF:

0.463

AC:

14995

AN:

32414

American (AMR)

AF:

0.0338

AC:

1477

AN:

43728

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

1250

AN:

25834

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39160

South Asian (SAS)

AF:

0.0319

AC:

2651

AN:

83026

European-Finnish (FIN)

AF:

0.000488

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.0815

AC:

467

AN:

5730

European-Non Finnish (NFE)

AF:

0.00935

AC:

10335

AN:

1105438

Other (OTH)

AF:

0.0443

AC:

2651

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1160

2321

3481

4642

5802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.138

AC:

20988

AN:

152112

Hom.:

4306

Cov.:

AF XY:

0.134

AC XY:

9959

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.450

AC:

18659

AN:

41424

American (AMR)

AF:

0.0681

AC:

1042

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0404

AC:

140

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0269

AC:

130

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0113

AC:

767

AN:

67980

Other (OTH)

AF:

0.102

AC:

215

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

634

1268

1903

2537

3171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0291

Hom.:

1751

Bravo

AF:

0.159

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.442

AC:

1949

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.0544

AC:

6601

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Nov 10, 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. -

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

not provided

Benign:3

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

- -

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;.;.;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.00076

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0014

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

.;.;.;M;M;.

PhyloP100

6.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

N;N;.;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.17

T;T;.;T;T;.

Sift4G

Benign

0.25

T;T;.;T;T;.

Polyphen

0.010

B;B;.;B;.;B

Vest4

0.40

MPC

0.29

ClinPred

0.021

GERP RS

4.9

Varity_R

0.15

gMVP

0.53

Mutation Taster

=92/8

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

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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