chr2-26477829-A-G

Position:

chr2-26477829-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_194322.3(OTOF):c.65T>C(p.Leu22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,581,032 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 13 hom. )

Consequence

OTOF
NM_194322.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.777

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074367225).

BP6

Variant 2-26477829-A-G is Benign according to our data. Variant chr2-26477829-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48189.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr2-26477829-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2215-80T>C		intron_variant		ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 linkuse as main transcript	c.-28+15T>C		intron_variant		ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2215-80T>C		intron_variant		1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.-28+15T>C		intron_variant		1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00267

AC:

519

AN:

194268

Hom.:

AF XY:

0.00249

AC XY:

260

AN XY:

104290

show subpopulations

Gnomad AFR exome

AF:

0.000955

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.00145

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000770

Gnomad FIN exome

AF:

0.000158

Gnomad NFE exome

AF:

0.00456

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00397

AC:

5675

AN:

1428770

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2728

AN XY:

707892

show subpopulations

Gnomad4 AFR exome

AF:

0.000614

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.00121

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000133

Gnomad4 FIN exome

AF:

0.000179

Gnomad4 NFE exome

AF:

0.00477

Gnomad4 OTH exome

AF:

0.00361

GnomAD4 genome

AF:

0.00263

AC:

401

AN:

152262

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00406

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00347

ExAC

AF:

0.00212

AC:

251

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOF: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2016	p.Leu22Pro in exon 1A of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (130/28336) of European chromos omes by the Exome Aggregation Consortium (http://exac.broadinstitute.org/; dbSNP rs143141993). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

OTOF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2022

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_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.66

DANN

Uncertain

0.99

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.26

M_CAP

Benign

0.043

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.95

Polyphen

0.020

ClinPred

0.037

GERP RS

2.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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