rs4665855

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000402415.8(OTOF):c.-110C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,576,720 control chromosomes in the GnomAD database, including 163,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18095 hom., cov: 32)

Exomes 𝑓: 0.44 ( 145627 hom. )

Consequence

OTOF
ENST00000402415.8 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.327

Publications

27 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=1.2123064E-6).

BP6

Variant 2-26477832-G-A is Benign according to our data. Variant chr2-26477832-G-A is described in ClinVar as Benign. ClinVar VariationId is 48191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2215-83C>T		intron_variant	Intron 18 of 46	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.-28+12C>T		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.2215-83C>T		intron_variant	Intron 18 of 46	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.-28+12C>T		intron_variant	Intron 1 of 28	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71619

AN:

151918

Hom.:

18076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.557

Gnomad AMR

AF:

0.573

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.563

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.440

GnomAD2 exomes

AF:

0.524

AC:

101448

AN:

193584

AF XY:

0.516

show subpopulations

Gnomad AFR exome

AF:

0.458

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.354

Gnomad EAS exome

AF:

0.987

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.459

GnomAD4 exome

AF:

0.438

AC:

623898

AN:

1424682

Hom.:

145627

Cov.:

AF XY:

0.440

AC XY:

310290

AN XY:

705488

show subpopulations

African (AFR)

AF:

0.447

AC:

14538

AN:

32522

American (AMR)

AF:

0.670

AC:

26004

AN:

38828

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

9039

AN:

25490

East Asian (EAS)

AF:

0.976

AC:

36580

AN:

37462

South Asian (SAS)

AF:

0.540

AC:

44431

AN:

82338

European-Finnish (FIN)

AF:

0.564

AC:

28191

AN:

50028

Middle Eastern (MID)

AF:

0.354

AC:

2027

AN:

5730

European-Non Finnish (NFE)

AF:

0.399

AC:

435841

AN:

1093212

Other (OTH)

AF:

0.461

AC:

27247

AN:

59072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

18589

37179

55768

74358

92947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13872

27744

41616

55488

69360

<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:

0.471

AC:

71682

AN:

152038

Hom.:

18095

Cov.:

AF XY:

0.484

AC XY:

35978

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.453

AC:

18789

AN:

41480

American (AMR)

AF:

0.574

AC:

8769

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1246

AN:

3470

East Asian (EAS)

AF:

0.984

AC:

5086

AN:

5170

South Asian (SAS)

AF:

0.564

AC:

2713

AN:

4814

European-Finnish (FIN)

AF:

0.594

AC:

6264

AN:

10550

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.402

AC:

27287

AN:

67956

Other (OTH)

AF:

0.445

AC:

938

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1858

3715

5573

7430

9288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.426

Hom.:

21793

Bravo

AF:

0.471

TwinsUK

AF:

0.382

AC:

1415

ALSPAC

AF:

0.405

AC:

1560

ESP6500AA

AF:

0.440

AC:

1167

ESP6500EA

AF:

0.394

AC:

1821

ExAC

AF:

0.472

AC:

55243

Asia WGS

AF:

0.746

AC:

2589

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro21Leu in exon 1 of OTOF: This variant is not expected to have clinical signif icance because it is has been identified in 5.4% (337/6988) of European American chromosomes and 28.3% (1051/3718) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs4665855). -

May 09, 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:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.0

(source)

DANN

Benign

0.65

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-1.0

PhyloP100

0.33

Polyphen

0.0

ClinPred

0.025

GERP RS

-0.57

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=96/4

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