2-26477447-C-T

Position:

chr2-26477447-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_194248.3(OTOF):c.2375G>A(p.Arg792Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000477 in 1,600,004 control chromosomes in the GnomAD database, including 5 homozygotes. 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. R792W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 3.86

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011497736).

BP6

Variant 2-26477447-C-T is Benign according to our data. Variant chr2-26477447-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48194.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=4, Likely_benign=2}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2375G>A	p.Arg792Gln	missense_variant	20/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.134G>A	p.Arg45Gln	missense_variant	3/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2375G>A	p.Arg792Gln	missense_variant	20/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.134G>A	p.Arg45Gln	missense_variant	3/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

250

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0161

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000676

AC:

153

AN:

226462

Hom.:

AF XY:

0.000580

AC XY:

AN XY:

122440

show subpopulations

Gnomad AFR exome

AF:

0.00519

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00126

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000528

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000355

AC:

514

AN:

1447816

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

249

AN XY:

718762

show subpopulations

Gnomad4 AFR exome

AF:

0.00495

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00112

Gnomad4 EAS exome

AF:

0.000204

Gnomad4 SAS exome

AF:

0.0000359

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152188

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00462

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000551

Hom.:

Bravo

AF:

0.00196

ESP6500AA

AF:

0.00484

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000707

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	The OTOF c.2375G>A; p.Arg792Gln variant (rs144800506), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 48194). This variant is found in the African population with an allele frequency of 0.49% (111/22,566 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at codon 792 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg792Gln variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2017

p.Arg792Gln in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (111/21722) of African chromos omes including 2 homozygotes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs144800506). -

OTOF-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as 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

0.13

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

.;.;.;T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.3

.;.;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.1

N;N;.;N;N;.

REVEL

Uncertain

0.56

Sift

Benign

0.048

D;D;.;D;D;.

Sift4G

Benign

0.067

T;T;.;T;T;.

Polyphen

0.64

P;B;.;P;.;D

Vest4

0.76

MVP

0.90

MPC

0.25

ClinPred

0.034

GERP RS

3.8

Varity_R

0.37

gMVP

0.36

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

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