NM_194248.3:c.4767C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_194248.3(OTOF):c.4767C>T(p.Arg1589Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,250 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 95 hom., cov: 33)

Exomes 𝑓: 0.011 ( 569 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -2.18

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-26465704-G-A is Benign according to our data. Variant chr2-26465704-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.18 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.4767C>T	p.Arg1589Arg	synonymous_variant	Exon 38 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.2466C>T	p.Arg822Arg	synonymous_variant	Exon 21 of 29	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.4767C>T	p.Arg1589Arg	synonymous_variant	Exon 38 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.2466C>T	p.Arg822Arg	synonymous_variant	Exon 21 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2377

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0426

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0420

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.0901

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00539

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0301

AC:

7569

AN:

251462

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.0402

Gnomad FIN exome

AF:

0.0872

Gnomad NFE exome

AF:

0.00571

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0107

AC:

15583

AN:

1461882

Hom.:

569

Cov.:

AF XY:

0.00986

AC XY:

7172

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33480

American (AMR)

AF:

0.108

AC:

4836

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00287

AC:

AN:

26136

East Asian (EAS)

AF:

0.0319

AC:

1267

AN:

39700

South Asian (SAS)

AF:

0.00341

AC:

294

AN:

86258

European-Finnish (FIN)

AF:

0.0829

AC:

4427

AN:

53414

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00354

AC:

3941

AN:

1112006

Other (OTH)

AF:

0.0114

AC:

686

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

981

1962

2943

3924

4905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<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:

0.0156

AC:

2379

AN:

152368

Hom.:

Cov.:

AF XY:

0.0194

AC XY:

1445

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41594

American (AMR)

AF:

0.0427

AC:

653

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.0424

AC:

220

AN:

5184

South Asian (SAS)

AF:

0.00373

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0901

AC:

956

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00539

AC:

367

AN:

68042

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00674

Hom.:

Bravo

AF:

0.0142

Asia WGS

AF:

0.0360

AC:

123

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Sep 26, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not expected to have clinical significance because it does not a lter an amino acid residue, is not located near a splice junction, and is report ed as a benign polymorphism (Varga 2006, Smith 2008). -

Oct 16, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.011

(source)

DANN

Benign

0.75

PhyloP100

-2.2

Mutation Taster

=92/8

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