rs80356569

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_194248.3(OTOF):c.2317C>T(p.Arg773Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,602,582 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 32)

Exomes 𝑓: 0.014 ( 227 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Splicing: ADA: 0.8316

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 7.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074848533).

BP6

Variant 2-26477505-G-A is Benign according to our data. Variant chr2-26477505-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477505-G-A is described in Lovd as [Benign]. Variant chr2-26477505-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	Exon 3 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.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2377

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0154

AC:

3504

AN:

227648

Hom.:

AF XY:

0.0158

AC XY:

1951

AN XY:

123548

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0518

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0235

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0139

AC:

20232

AN:

1450336

Hom.:

227

Cov.:

AF XY:

0.0144

AC XY:

10352

AN XY:

720362

show subpopulations

Gnomad4 AFR exome

AF:

0.0216

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.0541

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0230

Gnomad4 FIN exome

AF:

0.000782

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0156

AC:

2377

AN:

152246

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1140

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.0452

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0203

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.0129

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.0210

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.0145

AC:

1746

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22607986, 12114484, 16371502, 19461658) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 05, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

Jul 20, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

.;.;.;T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T;T

MetaRNN

Benign

0.0075

T;T;T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.3

.;.;.;M;M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

D;D;.;D;D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.014

D;D;.;D;D;.

Sift4G

Uncertain

0.031

D;D;.;D;D;.

Polyphen

0.17

B;D;.;D;.;D

Vest4

0.73

MPC

0.49

ClinPred

0.029

GERP RS

4.7

Varity_R

0.21

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Pathogenic

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over