rs1879761

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.158C>T(p.Ala53Val) variant causes a missense change. The variant allele was found at a frequency of 0.0227 in 1,613,822 control chromosomes in the GnomAD database, including 4,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 529 hom., cov: 32)

Exomes 𝑓: 0.022 ( 4160 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 5.06

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, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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=0.0017544031).

BP6

Variant 2-26527901-G-A is Benign according to our data. Variant chr2-26527901-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.158C>T	p.Ala53Val	missense	Exon 3 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.158C>T	p.Ala53Val	missense	Exon 3 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.158C>T	p.Ala53Val	missense	Exon 3 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.158C>T	p.Ala53Val	missense	Exon 3 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4884

AN:

152066

Hom.:

524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00279

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0655

AC:

16470

AN:

251374

AF XY:

0.0548

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.00289

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0218

AC:

31808

AN:

1461638

Hom.:

4160

Cov.:

AF XY:

0.0206

AC XY:

14987

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33474

American (AMR)

AF:

0.268

AC:

11967

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00130

AC:

AN:

26134

East Asian (EAS)

AF:

0.322

AC:

12771

AN:

39686

South Asian (SAS)

AF:

0.0204

AC:

1757

AN:

86252

European-Finnish (FIN)

AF:

0.0150

AC:

800

AN:

53418

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00240

AC:

2667

AN:

1111804

Other (OTH)

AF:

0.0280

AC:

1690

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1537

3074

4610

6147

7684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.0322

AC:

4894

AN:

152184

Hom.:

529

Cov.:

AF XY:

0.0372

AC XY:

2771

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00513

AC:

213

AN:

41528

American (AMR)

AF:

0.171

AC:

2606

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.291

AC:

1498

AN:

5144

South Asian (SAS)

AF:

0.0234

AC:

113

AN:

4820

European-Finnish (FIN)

AF:

0.0177

AC:

188

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00279

AC:

190

AN:

68012

Other (OTH)

AF:

0.0388

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

188

376

565

753

941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0140

Hom.:

461

Bravo

AF:

0.0460

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.0537

AC:

6520

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Autosomal recessive nonsyndromic hearing loss 9 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.094

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

5.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.18

Vest4

0.47

MPC

0.22

ClinPred

0.0084

GERP RS

4.5

Varity_R

0.18

gMVP

0.48

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over