rs111033329

Positions:

chr2-26461006-C-T

Variant summary

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

The ENST00000272371.7(OTOF):c.5558G>A(p.Arg1853Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,383,832 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1853R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0067 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0097 ( 60 hom. )

Consequence

OTOF
ENST00000272371.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.99

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=0.010482699).

BP6

Variant 2-26461006-C-T is Benign according to our data. Variant chr2-26461006-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48262.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5558G>A	p.Arg1853Gln	missense_variant	44/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.3257G>A	p.Arg1086Gln	missense_variant	27/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5558G>A	p.Arg1853Gln	missense_variant	44/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.3257G>A	p.Arg1086Gln	missense_variant	27/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

946

AN:

141304

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.0148

Gnomad AMR

AF:

0.00186

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00349

GnomAD3 exomes

AF:

0.00720

AC:

1805

AN:

250616

Hom.:

AF XY:

0.00717

AC XY:

972

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.00971

AC:

12062

AN:

1242432

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

5820

AN XY:

616088

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.00205

Gnomad4 ASJ exome

AF:

0.000566

Gnomad4 EAS exome

AF:

0.0000526

Gnomad4 SAS exome

AF:

0.0000712

Gnomad4 FIN exome

AF:

0.0280

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.00888

GnomAD4 genome

AF:

0.00669

AC:

946

AN:

141400

Hom.:

Cov.:

AF XY:

0.00674

AC XY:

461

AN XY:

68376

show subpopulations

Gnomad4 AFR

AF:

0.00146

Gnomad4 AMR

AF:

0.00186

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00345

Alfa

AF:

0.00856

Hom.:

Bravo

AF:

0.00496

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00852

AC:

1035

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00747

EpiControl

AF:

0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	OTOF: BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2011	This variant has not been reported in the literature, but it has now been identi fied in our laboratory in five individuals (5/265 or 1.9% of cases), none of who m have auditory neuropathy and three of whom have pathogenic variants in other g enes suggestive of another cause of hearing loss. In summary, the available data suggests this variant is benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

.;.;.;T;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.8

.;.;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

D;D;.;N;N;.

REVEL

Uncertain

0.52

Sift

Benign

0.22

T;T;.;T;T;.

Sift4G

Benign

0.18

T;T;.;T;T;.

Polyphen

0.96

P;P;.;D;.;D

Vest4

0.76

MVP

0.89

MPC

0.33

ClinPred

0.041

GERP RS

3.9

Varity_R

0.36

gMVP

0.61

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