Variant 2-26473186-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_194248.3(OTOF):c.3679C>T(p.Arg1227Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R1227R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

OTOF
NM_194248.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.755

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 Pathogenic. Variant got 12 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 2-26473186-G-A is Pathogenic according to our data. Variant chr2-26473186-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2734136.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.3679C>T	p.Arg1227Ter	stop_gained	29/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.1438C>T	p.Arg480Ter	stop_gained	12/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.3679C>T	p.Arg1227Ter	stop_gained	29/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.1438C>T	p.Arg480Ter	stop_gained	12/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249816

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460738

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 17, 2023

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with OTOF-related conditions (PMID: 26226137). This variant is present in population databases (rs111033478, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg1227*) 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.77

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.89

ClinPred

0.99

GERP RS

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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