rs111033427

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194248.3(OTOF):c.2215-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,612,286 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 33 hom. )

Consequence

OTOF
NM_194248.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.408

Publications

0 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 (BayesDel_noAF=-0.85).

BP6

Variant 2-26477768-G-C is Benign according to our data. Variant chr2-26477768-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 48188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00433 (659/152258) while in subpopulation AMR AF = 0.00804 (123/15294). AF 95% confidence interval is 0.00689. There are 1 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2215-19C>G		intron_variant	Intron 18 of 46	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.-27-19C>G		intron_variant	Intron 1 of 28	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.2215-19C>G		intron_variant	Intron 18 of 46	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.-27-19C>G		intron_variant	Intron 1 of 28	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

660

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00639

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00437

AC:

1084

AN:

248176

AF XY:

0.00449

show subpopulations

Gnomad AFR exome

AF:

0.000883

Gnomad AMR exome

AF:

0.00706

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00600

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00536

AC:

7825

AN:

1460028

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

3841

AN XY:

726292

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33468

American (AMR)

AF:

0.00689

AC:

308

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.000731

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00275

AC:

143

AN:

52044

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00623

AC:

6931

AN:

1111758

Other (OTH)

AF:

0.00459

AC:

277

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

432

865

1297

1730

2162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00433

AC:

659

AN:

152258

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41548

American (AMR)

AF:

0.00804

AC:

123

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00638

AC:

434

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.00438

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00749

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOF: BS2 -

not specified

Benign:2

Oct 08, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr42Thr in exon 1A of OTOF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.7% (57/8531) of Eur opean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs111033427). -

OTOF-related disorder

Benign:1

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.4

(source)

DANN

Benign

0.45

PhyloP100

-0.41

PromoterAI

0.062

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs111033427

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