NM_194248.3:c.2498A>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_194248.3(OTOF):c.2498A>T(p.Gln833Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,610,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.65

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041678667).

BP6

Variant 2-26477197-T-A is Benign according to our data. Variant chr2-26477197-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178511.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000591 (862/1458644) while in subpopulation SAS AF= 0.00227 (195/85884). AF 95% confidence interval is 0.00201. There are 1 homozygotes in gnomad4_exome. There are 496 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2498A>T	p.Gln833Leu	missense_variant	Exon 21 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.257A>T	p.Gln86Leu	missense_variant	Exon 4 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.2498A>T	p.Gln833Leu	missense_variant	Exon 21 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.257A>T	p.Gln86Leu	missense_variant	Exon 4 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000552

AC:

135

AN:

244384

Hom.:

AF XY:

0.000631

AC XY:

AN XY:

133184

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00243

Gnomad FIN exome

AF:

0.000342

Gnomad NFE exome

AF:

0.000417

Gnomad OTH exome

AF:

0.000671

GnomAD4 exome

AF:

0.000591

AC:

862

AN:

1458644

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

496

AN XY:

725470

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00227

Gnomad4 FIN exome

AF:

0.000293

Gnomad4 NFE exome

AF:

0.000553

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000269

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000548

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:2

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided

Uncertain:1Benign:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Mar 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln833Leu in exon 21 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (36/14280) of South Asian Chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs191568463). -

OTOF-related disorder

Benign:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Benign

0.099

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;.;.;T;.;.

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.59

T;T;T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.042

T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.0

.;.;.;M;M;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.3

D;D;.;D;D;.

REVEL

Uncertain

0.57

Sift

Benign

0.14

T;T;.;T;T;.

Sift4G

Benign

0.21

T;T;.;T;T;.

Polyphen

0.016

B;B;.;B;.;P

Vest4

0.63

MVP

0.89

MPC

0.16

ClinPred

0.027

GERP RS

5.0

Varity_R

0.80

gMVP

0.50

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