rs61746568

Positions:

chr2-26527914-G-A

Variant summary

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

The NM_194248.3(OTOF):c.145C>T(p.Arg49Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,613,334 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 55 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.07

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=0.0154441).

BP6

Variant 2-26527914-G-A is Benign according to our data. Variant chr2-26527914-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26527914-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00666 (1014/152312) while in subpopulation AMR AF= 0.0228 (349/15308). AF 95% confidence interval is 0.0208. There are 8 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.145C>T	p.Arg49Trp	missense_variant	3/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 linkuse as main transcript	c.145C>T	p.Arg49Trp	missense_variant	3/46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.145C>T	p.Arg49Trp	missense_variant	3/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.145C>T	p.Arg49Trp	missense_variant	3/46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

1016

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00811

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00956

AC:

2403

AN:

251460

Hom.:

AF XY:

0.00857

AC XY:

1165

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00812

Gnomad AMR exome

AF:

0.0354

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.0153

Gnomad SAS exome

AF:

0.00784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00433

AC:

6323

AN:

1461022

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

3258

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00721

Gnomad4 AMR exome

AF:

0.0341

Gnomad4 ASJ exome

AF:

0.0179

Gnomad4 EAS exome

AF:

0.0199

Gnomad4 SAS exome

AF:

0.00874

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00184

Gnomad4 OTH exome

AF:

0.00639

GnomAD4 genome

AF:

0.00666

AC:

1014

AN:

152312

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

510

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00806

Gnomad4 AMR

AF:

0.0228

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.0162

Gnomad4 SAS

AF:

0.00993

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.00834

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00838

AC:

1017

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 17, 2011	Arg49Trp in exon 3 of OTOF: This variant is not expected to have clinical signif icance due to an equal occurrence in Chinese proband chromosomes 2/146 (1.4%) an d ethnically matched control chromosomes 4/184 (2.2%) (Wang 2010). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2019	- -
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	Jul 01, 2024	OTOF: BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 9

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 28, 2022	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.86

MVP

0.92

MPC

0.67

ClinPred

0.014

GERP RS

5.4

Varity_R

0.47

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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