NM_194248.3:c.245G>A

Variant names:

Variant summary

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

The NM_194248.3(OTOF):c.245G>A(p.Arg82His) variant causes a missense change. The variant allele was found at a frequency of 0.000478 in 1,603,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R82C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 3.68

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=0.01242134).

BP6

Variant 2-26519092-C-T is Benign according to our data. Variant chr2-26519092-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00216 (329/152294) while in subpopulation AFR AF= 0.0071 (295/41572). AF 95% confidence interval is 0.00643. There are 1 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.245G>A	p.Arg82His	missense_variant	Exon 4 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.245G>A	p.Arg82His	missense_variant	Exon 4 of 46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.245G>A	p.Arg82His	missense_variant	Exon 4 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.245G>A	p.Arg82His	missense_variant	Exon 4 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

329

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00712

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000505

AC:

118

AN:

233884

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

126342

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.000537

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000775

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000301

AC:

437

AN:

1450854

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

190

AN XY:

720778

show subpopulations

Gnomad4 AFR exome

AF:

0.00716

Gnomad4 AMR exome

AF:

0.000660

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000684

GnomAD4 genome

AF:

0.00216

AC:

329

AN:

152294

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00710

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000353

Hom.:

Bravo

AF:

0.00250

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000545

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Aug 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R82H variant in the OTOF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It is reported as benign in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000065194.4; Landrum et al., 2015). The R82H variant is observed in 50/7412 (0.68%) alleles from individuals of African background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The R82H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R82H as a variant of uncertain significance. -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: BP4, BS2 -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:2

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. -

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

May 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg82His in Exon 04 of OTOF: This variant is not expected to have clinical signi ficance because it has been identified in 0.6% (24/3738) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs149766574). -

Apr 30, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood onset hearing loss

Uncertain:1

Jul 08, 2021

National Institute on Deafness and Communication Disorders, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

OTOF-related disorder

Benign:1

Dec 24, 2019

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

0.084

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.097

T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.23

Sift

Benign

0.096

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.94

P;.

Vest4

0.54

MVP

0.92

MPC

0.62

ClinPred

0.027

GERP RS

5.1

Varity_R

0.13

gMVP

0.35

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