2-26474554-C-G

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.3247G>C(p.Ala1083Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,612,842 control chromosomes in the GnomAD database, including 374 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1083T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 20 hom., cov: 31)

Exomes 𝑓: 0.019 ( 354 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.494

Publications

9 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=0.005121857).

BP6

Variant 2-26474554-C-G is Benign according to our data. Variant chr2-26474554-C-G is described in ClinVar as Benign. ClinVar VariationId is 21844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (2245/152340) while in subpopulation NFE AF = 0.0195 (1329/68028). AF 95% confidence interval is 0.0187. There are 20 homozygotes in GnomAd4. There are 1020 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.3247G>C	p.Ala1083Pro	missense_variant	Exon 26 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 link	c.1006G>C	p.Ala336Pro	missense_variant	Exon 9 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.3247G>C	p.Ala1083Pro	missense_variant	Exon 26 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8 link	c.1006G>C	p.Ala336Pro	missense_variant	Exon 9 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2243

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00921

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0145

AC:

3606

AN:

249378

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.00740

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0195

AC:

28469

AN:

1460502

Hom.:

354

Cov.:

AF XY:

0.0190

AC XY:

13770

AN XY:

726540

show subpopulations

African (AFR)

AF:

0.00884

AC:

296

AN:

33470

American (AMR)

AF:

0.00786

AC:

351

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

538

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00321

AC:

277

AN:

86226

European-Finnish (FIN)

AF:

0.0228

AC:

1191

AN:

52338

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0222

AC:

24738

AN:

1111832

Other (OTH)

AF:

0.0168

AC:

1016

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1461

2922

4383

5844

7305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

936

1872

2808

3744

4680

<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:

0.0147

AC:

2245

AN:

152340

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1020

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00926

AC:

385

AN:

41580

American (AMR)

AF:

0.0123

AC:

189

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0195

AC:

1329

AN:

68028

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

107

213

320

426

533

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:

0.00863

Hom.:

Bravo

AF:

0.0143

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0233

AC:

200

ExAC

AF:

0.0143

AC:

1735

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0222

EpiControl

AF:

0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16371502, 18381613, 20301429) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not specified

Benign:1

Oct 06, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala1083Pro in exon 26 of OTOF: This variant is not expected to have clinical sig nificance because this residue is not highly conserved across species and this v ariant has been reported as benign in two publications (Varga 2006, Rodriguez-Ba llesteros 2008). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

MetaRNN

Benign

0.0051

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

.;.;.;L;L;.

PhyloP100

0.49

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

N;N;.;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.27

T;T;.;T;T;.

Sift4G

Benign

0.27

T;T;.;T;T;.

Polyphen

0.28

B;P;.;P;.;P

Vest4

0.29

MPC

0.31

ClinPred

0.0060

GERP RS

4.9

Varity_R

0.25

gMVP

0.62

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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