2-26479541-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_194248.3(OTOF):c.2025G>A(p.Glu675Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,611,448 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 79 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.461

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-26479541-C-T is Benign according to our data. Variant chr2-26479541-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.461 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00778 (1185/152298) while in subpopulation AMR AF = 0.0122 (187/15306). AF 95% confidence interval is 0.0108. There are 9 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2025G>A	p.Glu675Glu	synonymous_variant	Exon 17 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.2025G>A	p.Glu675Glu	synonymous_variant	Exon 17 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.2025G>A	p.Glu675Glu	synonymous_variant	Exon 17 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.2025G>A	p.Glu675Glu	synonymous_variant	Exon 17 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00780

AC:

1187

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00913

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00793

AC:

1942

AN:

244822

AF XY:

0.00781

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00612

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0100

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00874

AC:

12759

AN:

1459150

Hom.:

Cov.:

AF XY:

0.00881

AC XY:

6394

AN XY:

725712

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33468

American (AMR)

AF:

0.00591

AC:

263

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.0197

AC:

513

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00214

AC:

184

AN:

85896

European-Finnish (FIN)

AF:

0.0101

AC:

524

AN:

52006

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00949

AC:

10550

AN:

1111492

Other (OTH)

AF:

0.00965

AC:

582

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

762

1525

2287

3050

3812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.00778

AC:

1185

AN:

152298

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

615

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41576

American (AMR)

AF:

0.0122

AC:

187

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00913

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

747

AN:

68024

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

121

181

242

302

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:

0.0102

Hom.:

Bravo

AF:

0.00667

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jul 26, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOF: BP4, BP7, BS2 -

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 11, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.8

(source)

DANN

Benign

0.33

PhyloP100

0.46

Mutation Taster

=99/1

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