2-26537756-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_194248.3(OTOF):c.98G>A(p.Arg33Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,554,618 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 7 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.97

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009204447).

BP6

Variant 2-26537756-C-T is Benign according to our data. Variant chr2-26537756-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48278.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00675 (1027/152204) while in subpopulation AFR AF = 0.0233 (966/41524). AF 95% confidence interval is 0.022. There are 10 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.98G>A	p.Arg33Gln	missense_variant	Exon 2 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2 link	c.98G>A	p.Arg33Gln	missense_variant	Exon 2 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.98G>A	p.Arg33Gln	missense_variant	Exon 2 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7 link	c.98G>A	p.Arg33Gln	missense_variant	Exon 2 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes

AF:

0.00673

AC:

1023

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00195

AC:

315

AN:

161902

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000851

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00176

GnomAD4 exome

AF:

0.000762

AC:

1068

AN:

1402414

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

474

AN XY:

692062

show subpopulations

African (AFR)

AF:

0.0235

AC:

745

AN:

31720

American (AMR)

AF:

0.00253

AC:

AN:

36414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25230

East Asian (EAS)

AF:

0.0000277

AC:

AN:

36042

South Asian (SAS)

AF:

0.0000756

AC:

AN:

79406

European-Finnish (FIN)

AF:

0.0000404

AC:

AN:

49510

Middle Eastern (MID)

AF:

0.00333

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000935

AC:

101

AN:

1080270

Other (OTH)

AF:

0.00175

AC:

102

AN:

58122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00675

AC:

1027

AN:

152204

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

506

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0233

AC:

966

AN:

41524

American (AMR)

AF:

0.00268

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67996

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00321

Hom.:

Bravo

AF:

0.00791

ESP6500AA

AF:

0.0187

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00124

AC:

136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19461658, 29362361) -

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg33Gln in exon 2 of OTOF: This variant has been reported in one study after id entification in a single hearing loss proband (Romanos 2006). However, this vari ant is not expected to have clinical significance because it is present in the d bSNP database (rs56332208) with a frequency of 6.8% (8/118 chromosomes) in the Y RI HapMap population and 1.1% (34/3098) in the ESP North American cohort. -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

4.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.63

N;N

REVEL

Uncertain

0.29

Sift

Uncertain

0.022

D;D

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;.

Vest4

0.63

MVP

0.92

MPC

0.70

ClinPred

0.021

GERP RS

4.8

Varity_R

0.23

gMVP

0.45

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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