rs55676840

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA142762/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0089 ( 17 hom., cov: 33)

Exomes 𝑓: 0.012 ( 177 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9O:1

Conservation

PhyloP100: 5.00

Publications

11 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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.1723G>A	p.Val575Met	missense_variant	Exon 15 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.1723G>A	p.Val575Met	missense_variant	Exon 15 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.1723G>A	p.Val575Met	missense_variant	Exon 15 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.1723G>A	p.Val575Met	missense_variant	Exon 15 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00887

AC:

1350

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0435

Gnomad FIN

AF:

0.00847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.0121

AC:

3025

AN:

249328

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00944

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0123

AC:

18023

AN:

1460734

Hom.:

177

Cov.:

AF XY:

0.0131

AC XY:

9526

AN XY:

726646

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33480

American (AMR)

AF:

0.00304

AC:

136

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0378

AC:

3257

AN:

86256

European-Finnish (FIN)

AF:

0.0107

AC:

560

AN:

52300

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0119

AC:

13241

AN:

1111994

Other (OTH)

AF:

0.0116

AC:

700

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1142

2285

3427

4570

5712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.00886

AC:

1349

AN:

152282

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

683

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41564

American (AMR)

AF:

0.00379

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.0433

AC:

209

AN:

4824

European-Finnish (FIN)

AF:

0.00847

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

832

AN:

67998

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

133

200

266

333

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:

0.0104

Hom.:

Bravo

AF:

0.00778

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.0130

AC:

1577

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00900

EpiControl

AF:

0.00972

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 12, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Oct 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. -

Jan 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val575Met in exon 15 of OTOF: This variant is not expected to have clinical sign ificance because it has been reported as a neutral change (Varga 2006, Smith 200 8), is present in dbSNP (rs55676840 ? 4 entries), adn has been identified in our laboratory in ~3% of patients. -

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

- -

Nonsyndromic genetic hearing loss

Benign:1

May 13, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

5.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.28

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.80

P;.

Vest4

0.45

MPC

0.26

ClinPred

0.077

GERP RS

4.5

Varity_R

0.26

gMVP

0.76

Mutation Taster

=93/7

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