rs55639868

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_194248.3(OTOF):c.710+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,840 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0088 ( 7 hom., cov: 33)

Exomes 𝑓: 0.010 ( 87 hom. )

Consequence

OTOF
NM_194248.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -1.39

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-26502290-G-A is Benign according to our data. Variant chr2-26502290-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48273.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00884 (1347/152306) while in subpopulation NFE AF = 0.0136 (928/68018). AF 95% confidence interval is 0.0129. There are 7 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.710+10C>T		intron_variant	Intron 7 of 46	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.710+10C>T		intron_variant	Intron 7 of 45		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.710+10C>T		intron_variant	Intron 7 of 46	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.710+10C>T		intron_variant	Intron 7 of 45	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00999

AC:

2506

AN:

250932

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00943

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00303

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0102

AC:

14939

AN:

1461534

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

7528

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33472

American (AMR)

AF:

0.0103

AC:

459

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

690

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00435

AC:

375

AN:

86232

European-Finnish (FIN)

AF:

0.00396

AC:

211

AN:

53314

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0111

AC:

12374

AN:

1111890

Other (OTH)

AF:

0.0116

AC:

702

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

752

1504

2256

3008

3760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.00884

AC:

1347

AN:

152306

Hom.:

Cov.:

AF XY:

0.00851

AC XY:

634

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41560

American (AMR)

AF:

0.00961

AC:

147

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0136

AC:

928

AN:

68018

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0117

Hom.:

Bravo

AF:

0.00842

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 08, 2017

GeneDx

Significance:Likely 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 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

710+10C>T in exon 7 of OTOF: This variant is not expected to have clinical signi ficance because it is not located within the splice consensus sequence, has been identified in 1.4% (96/7020) of European American chromosomes and 0.2% (8/3738) of African American chromosomes in a broad population by the NHLBI Exome sequen cing project (http://evs.gs.washington.edu/EVS/; dbSNP rs55639868). -

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

- -

not provided

Benign:4

Feb 27, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

5.9

(source)

DANN

Benign

0.59

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(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