NM_194248.3:c.5558G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_194248.3(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).

Frequency

Genomes: 𝑓 0.0067 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0097 ( 60 hom. )

Consequence

OTOF
NM_194248.3 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 -11 ACMG points.

PM1

In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3

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}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00669 (946/141400) while in subpopulation NFE AF= 0.0101 (658/65122). AF 95% confidence interval is 0.00946. There are 4 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.3257G>A	p.Arg1086Gln	missense_variant	Exon 27 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.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.3257G>A	p.Arg1086Gln	missense_variant	Exon 27 of 29	1	NM_194323.3	ENSP00000344521.3		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

Jun 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: BS1, BS2 -

not specified

Benign:2

Feb 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

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. -

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;.

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