rs140454738

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_194248.3(OTOF):c.446C>T(p.Thr149Met) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T149T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.39

Publications

7 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15039575).

BP6

Variant 2-26516481-G-A is Benign according to our data. Variant chr2-26516481-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48236.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.446C>T	p.Thr149Met	missense_variant	Exon 5 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.446C>T	p.Thr149Met	missense_variant	Exon 5 of 46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.446C>T	p.Thr149Met	missense_variant	Exon 5 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.446C>T	p.Thr149Met	missense_variant	Exon 5 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000291

AC:

AN:

251278

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000218

AC:

318

AN:

1461618

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00283

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53166

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000166

AC:

185

AN:

1111994

Other (OTH)

AF:

0.000315

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000145

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.000327

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000433

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Jan 25, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr149Met in exon 5A of OTOF: This variant is not expected to have clinical si gnificance because it has also been identified in 0.34% (35/10152) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org/; dbSNP rs140454738). It has also been identified in 1 individua l with Usher syndrome who was found to have an alternate genetic etiology for Us her syndrome. ACMG/AMP criteria applied: BS1; BP5; PP3. -

OTOF-related disorder

Benign:1

May 21, 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

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

0.052

MutationAssessor

Benign

0.81

L;L

PhyloP100

6.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.11

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.99

D;.

Vest4

0.70

MVP

0.95

MPC

0.67

ClinPred

0.11

GERP RS

5.5

Varity_R

0.077

gMVP

0.37

Mutation Taster

=76/24

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

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