rs111033393

Positions:

chr2-26464004-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP3BP4_StrongBP6

The NM_194248.3(OTOF):c.5063C>T(p.Thr1688Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1688K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 8.10

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:

OTOF (HGNC:):

OTOF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.054777652).

BP6

Variant 2-26464004-G-A is Benign according to our data. Variant chr2-26464004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48248.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5063C>T	p.Thr1688Met	missense_variant	40/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 linkuse as main transcript	c.2762C>T	p.Thr921Met	missense_variant	23/29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5063C>T	p.Thr1688Met	missense_variant	40/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.2762C>T	p.Thr921Met	missense_variant	23/29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00126

AC:

315

AN:

250620

Hom.:

AF XY:

0.00133

AC XY:

180

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00143

AC:

2095

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1004

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000358

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152290

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00210

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported in association with hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 19461658) -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2012	Thr1688Met in exon 40 of OTOF: This variant has been identified in three individ uals by our laboratory, none of whom had second OTOF variants and one of whom ha d another cause of hearing loss. In addition, this variant has been identified i n 0.19% (16/8600) of European American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs11103 3393). In summary, these data suggest this variant is likely benign. -

OTOF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;.;.;D;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.055

T;T;T;T;T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.0

.;.;.;M;M;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.4

D;D;.;D;D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;.;D;D;.

Polyphen

0.99

D;D;.;D;.;D

Vest4

0.83

MVP

0.94

MPC

0.60

ClinPred

0.034

GERP RS

4.4

Varity_R

0.53

gMVP

0.80

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

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