rs111033329

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_194248.3(OTOF):c.5558G>A(p.Arg1853Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,383,832 control chromosomes in the GnomAD database, including 64 homozygotes. 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. R1853R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0067 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0097 ( 60 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.99

Publications

8 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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_194248.3

BP4

Computational evidence support a benign effect (MetaRNN=0.010482699).

BP6

Variant 2-26461006-C-T is Benign according to our data. Variant chr2-26461006-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48262.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00669 (946/141400) while in subpopulation NFE AF = 0.0101 (658/65122). AF 95% confidence interval is 0.00946. There are 4 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.3257G>A	p.Arg1086Gln	missense_variant	Exon 27 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.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.3257G>A	p.Arg1086Gln	missense_variant	Exon 27 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

946

AN:

141304

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.0148

Gnomad AMR

AF:

0.00186

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00349

GnomAD2 exomes

AF:

0.00720

AC:

1805

AN:

250616

AF XY:

0.00717

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.00971

AC:

12062

AN:

1242432

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

5820

AN XY:

616088

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

26952

American (AMR)

AF:

0.00205

AC:

AN:

38004

Ashkenazi Jewish (ASJ)

AF:

0.000566

AC:

AN:

17680

East Asian (EAS)

AF:

0.0000526

AC:

AN:

19014

South Asian (SAS)

AF:

0.0000712

AC:

AN:

84234

European-Finnish (FIN)

AF:

0.0280

AC:

988

AN:

35282

Middle Eastern (MID)

AF:

0.00196

AC:

AN:

4592

European-Non Finnish (NFE)

AF:

0.0108

AC:

10518

AN:

971058

Other (OTH)

AF:

0.00888

AC:

405

AN:

45616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

632

1264

1897

2529

3161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.00669

AC:

946

AN:

141400

Hom.:

Cov.:

AF XY:

0.00674

AC XY:

461

AN XY:

68376

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

38940

American (AMR)

AF:

0.00186

AC:

AN:

13984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3344

East Asian (EAS)

AF:

0.00

AC:

AN:

4152

South Asian (SAS)

AF:

0.00

AC:

AN:

3984

European-Finnish (FIN)

AF:

0.0213

AC:

185

AN:

8690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0101

AC:

658

AN:

65122

Other (OTH)

AF:

0.00345

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00849

Hom.:

Bravo

AF:

0.00496

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00852

AC:

1035

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00747

EpiControl

AF:

0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOF: BS1, BS2 -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature, but it has now been identi fied in our laboratory in five individuals (5/265 or 1.9% of cases), none of who m have auditory neuropathy and three of whom have pathogenic variants in other g enes suggestive of another cause of hearing loss. In summary, the available data suggests this variant is benign. -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

.;.;.;T;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.8

.;.;.;M;M;.

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

D;D;.;N;N;.

REVEL

Uncertain

0.52

Sift

Benign

0.22

T;T;.;T;T;.

Sift4G

Benign

0.18

T;T;.;T;T;.

Polyphen

0.96

P;P;.;D;.;D

Vest4

0.76

MVP

0.89

MPC

0.33

ClinPred

0.041

GERP RS

3.9

Varity_R

0.36

gMVP

0.61

Mutation Taster

=91/9

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