2-26474622-GC-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_194248.3(OTOF):c.3178delG(p.Ala1060GlnfsTer86) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

OTOF
NM_194248.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.13

Publications

1 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-26474622-GC-G is Pathogenic according to our data. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474622-GC-G is described in CliVar as Pathogenic. Clinvar id is 179115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.3178delG	p.Ala1060GlnfsTer86	frameshift_variant	Exon 26 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.937delG	p.Ala313GlnfsTer86	frameshift_variant	Exon 9 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.3178delG	p.Ala1060GlnfsTer86	frameshift_variant	Exon 26 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.937delG	p.Ala313GlnfsTer86	frameshift_variant	Exon 9 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461012

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ala1060Glnfs*86) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OTOF-related conditions. ClinVar contains an entry for this variant (Variation ID: 179115). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Aug 01, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ala1060fs variant in OTOF has not been reported in individuals with hearing loss or in large population studies. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 1060 and lead to a pr emature termination codon 86 amino acids downstream. This alteration is then pre dicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over