rs116525289

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_194248.3(OTOF):c.129C>T(p.Asp43Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 1,554,472 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 71 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 453 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.56

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-26537725-G-A is Benign according to our data. Variant chr2-26537725-G-A is described in ClinVar as Benign. ClinVar VariationId is 48167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2 link	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7 link	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2659

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0137

AC:

2224

AN:

162332

AF XY:

0.0130

show subpopulations

Gnomad AFR exome

AF:

0.0404

Gnomad AMR exome

AF:

0.00423

Gnomad ASJ exome

AF:

0.000347

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.00653

AC:

9156

AN:

1402208

Hom.:

453

Cov.:

AF XY:

0.00655

AC XY:

4536

AN XY:

692044

show subpopulations

African (AFR)

AF:

0.0402

AC:

1274

AN:

31702

American (AMR)

AF:

0.00486

AC:

177

AN:

36418

Ashkenazi Jewish (ASJ)

AF:

0.000277

AC:

AN:

25232

East Asian (EAS)

AF:

0.143

AC:

5162

AN:

35998

South Asian (SAS)

AF:

0.0107

AC:

853

AN:

79408

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

49462

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000852

AC:

920

AN:

1080198

Other (OTH)

AF:

0.0112

AC:

649

AN:

58094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

473

946

1419

1892

2365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.0174

AC:

2652

AN:

152264

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1327

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0418

AC:

1735

AN:

41544

American (AMR)

AF:

0.00843

AC:

129

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.117

AC:

603

AN:

5170

South Asian (SAS)

AF:

0.00973

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

68004

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

125

250

376

501

626

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:

0.00653

Hom.:

Bravo

AF:

0.0193

Asia WGS

AF:

0.0440

AC:

151

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 27, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp43Asp in exon 2 of OTOF: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue, is not located within th e splice consensus sequence, has been identified in 3.2% (118/3708) of African A merican chromosomes from a broad population by the NHLBI Exome sequencing projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs116525289).

Oct 25, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 03, 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.

not provided

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal recessive nonsyndromic hearing loss 9

Benign: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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.6

Mutation Taster

=100/0

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