rs41288773

Positions:

chr2-26472632-A-C

Variant summary

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

The NM_194248.3(OTOF):c.3751T>G(p.Cys1251Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,122 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 33)

Exomes 𝑓: 0.022 ( 384 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.62

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 (MetaRNN=0.0041293204).

BP6

Variant 2-26472632-A-C is Benign according to our data. Variant chr2-26472632-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 48225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26472632-A-C is described in Lovd as [Benign]. Variant chr2-26472632-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2317/152342) while in subpopulation NFE AF= 0.0241 (1642/68032). AF 95% confidence interval is 0.0232. There are 19 homozygotes in gnomad4. There are 1046 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.3751T>G	p.Cys1251Gly	missense_variant	30/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.1493-43T>G		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 link	c.3751T>G	p.Cys1251Gly	missense_variant	30/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.1493-43T>G		intron_variant		1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2319

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0157

AC:

3927

AN:

249600

Hom.:

AF XY:

0.0164

AC XY:

2219

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00600

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00598

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0217

AC:

31685

AN:

1460780

Hom.:

384

Cov.:

AF XY:

0.0213

AC XY:

15512

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.00355

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.00543

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00691

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0152

AC:

2317

AN:

152342

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1046

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00476

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0158

Gnomad4 NFE

AF:

0.0241

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0205

Hom.:

Bravo

AF:

0.0147

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0198

AC:

170

ExAC

AF:

0.0166

AC:

2013

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	OTOF: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	This variant is associated with the following publications: (PMID: 27766948, 19461658) -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	Cys1251Gly in exon 30 of OTOF: This variant is predicted to be benign based on i ts high frequency in the general population (rs41288773; heterozyogous frequency = 2.5%). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 02, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.8

DANN

Benign

0.50

DEOGEN2

Benign

0.032

.;T;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.51

T;T;T;T

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

.;N;N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.21

.;N;N;.

REVEL

Benign

0.21

Sift

Benign

0.39

.;T;T;.

Sift4G

Benign

0.46

.;T;T;.

Polyphen

0.0

.;B;.;B

Vest4

0.17, 0.087

MPC

0.19

ClinPred

0.0030

GERP RS

-4.8

Varity_R

0.045

gMVP

0.44

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

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