2-26477447-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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 Uncertain significance.

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:5

Conservation

PhyloP100: 3.86

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 48194.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00164 (249/152188) while in subpopulation AFR AF = 0.00462 (192/41546). AF 95% confidence interval is 0.00409. There are 2 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2375G>A	p.Arg792Gln	missense_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.134G>A	p.Arg45Gln	missense_variant	Exon 3 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.2375G>A	p.Arg792Gln	missense_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.134G>A	p.Arg45Gln	missense_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3		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

GnomAD2 exomes

AF:

0.000676

AC:

153

AN:

226462

AF XY:

0.000580

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 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

African (AFR)

AF:

0.00495

AC:

165

AN:

33300

American (AMR)

AF:

0.00121

AC:

AN:

42934

Ashkenazi Jewish (ASJ)

AF:

0.00112

AC:

AN:

25812

East Asian (EAS)

AF:

0.000204

AC:

AN:

39204

South Asian (SAS)

AF:

0.0000359

AC:

AN:

83674

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51152

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000165

AC:

182

AN:

1106108

Other (OTH)

AF:

0.00107

AC:

AN:

59904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152188

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00462

AC:

192

AN:

41546

American (AMR)

AF:

0.00150

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67986

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000664

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:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Jun 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTOF c.2375G>A (p.Arg792Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 226462 control chromosomes, predominantly at a frequency of 0.0052 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011). To our knowledge, no occurrence of c.2375G>A in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 48194). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1

Jan 13, 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. -

OTOF-related disorder

Benign:1

Dec 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

3.9

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

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over