ENST00000402415.8:c.-46C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000402415.8(OTOF):c.-46C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,612,286 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 33 hom. )

Consequence

OTOF
ENST00000402415.8 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.408

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 2-26477768-G-C is Benign according to our data. Variant chr2-26477768-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 48188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477768-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00433 (659/152258) while in subpopulation AMR AF= 0.00804 (123/15294). AF 95% confidence interval is 0.00689. There are 1 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2215-19C>G		intron_variant	Intron 18 of 46	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.-27-19C>G		intron_variant	Intron 1 of 28	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.2215-19C>G		intron_variant	Intron 18 of 46	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.-27-19C>G		intron_variant	Intron 1 of 28	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

660

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00639

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00437

AC:

1084

AN:

248176

Hom.:

AF XY:

0.00449

AC XY:

606

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.000883

Gnomad AMR exome

AF:

0.00706

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000886

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00600

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00536

AC:

7825

AN:

1460028

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

3841

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00689

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.00623

Gnomad4 OTH exome

AF:

0.00459

GnomAD4 genome

AF:

0.00433

AC:

659

AN:

152258

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00804

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00349

Gnomad4 NFE

AF:

0.00638

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.00438

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00749

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Jun 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr42Thr in exon 1A of OTOF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.7% (57/8531) of Eur opean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs111033427). -

Oct 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OTOF-related disorder

Benign:1

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.4

DANN

Benign

0.45

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

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