chr2-26473506-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.3470G>A(p.Arg1157Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,612,842 control chromosomes in the GnomAD database, including 146 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. R1157W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0085 ( 7 hom., cov: 33)

Exomes 𝑓: 0.013 ( 139 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 2.76

Publications

10 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=0.0115759075).

BP6

Variant 2-26473506-C-T is Benign according to our data. Variant chr2-26473506-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21845.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00847 (1290/152238) while in subpopulation NFE AF = 0.0146 (990/68002). AF 95% confidence interval is 0.0138. There are 7 homozygotes in GnomAd4. There are 538 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.3470G>A	p.Arg1157Gln	missense_variant	Exon 28 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.1229G>A	p.Arg410Gln	missense_variant	Exon 11 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.3470G>A	p.Arg1157Gln	missense_variant	Exon 28 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.1229G>A	p.Arg410Gln	missense_variant	Exon 11 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00849

AC:

1291

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00809

AC:

2022

AN:

250062

AF XY:

0.00793

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.00955

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00146

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0129

AC:

18796

AN:

1460604

Hom.:

139

Cov.:

AF XY:

0.0124

AC XY:

9043

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33480

American (AMR)

AF:

0.0101

AC:

451

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000870

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

52280

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0156

AC:

17295

AN:

1111922

Other (OTH)

AF:

0.0116

AC:

701

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1015

2030

3045

4060

5075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.00847

AC:

1290

AN:

152238

Hom.:

Cov.:

AF XY:

0.00723

AC XY:

538

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41536

American (AMR)

AF:

0.00974

AC:

149

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

990

AN:

68002

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00954

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0150

AC:

129

ExAC

AF:

0.00798

AC:

969

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

May 03, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg1157Gln in exon 28 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (50/6794) of chromosomes from a broad population (dbSNP rs56054534). In addition, this variant has been reporte d in the literature and is not expected to have clinical significance due to an equal occurrence in probands and controls (Smith 2008, Varga 2006). -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOF: BS1, BS2 -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20230791, 16371502, 27766948) -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

.;.;.;T;.;.

Eigen

Benign

-0.053

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

-0.99

.;.;.;N;N;.

PhyloP100

2.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

N;N;.;N;N;.

REVEL

Uncertain

0.36

Sift

Benign

1.0

T;T;.;T;T;.

Sift4G

Benign

1.0

T;T;.;T;T;.

Polyphen

0.30

B;P;.;D;.;D

Vest4

0.37

MVP

0.88

MPC

0.71

ClinPred

0.013

GERP RS

5.2

PromoterAI

0.042

Neutral

(source)

Varity_R

0.25

gMVP

0.69

Mutation Taster

=96/4

polymorphism

(source)

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

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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