rs45442103

Positions:

chr2-26460909-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_194248.3(OTOF):c.5655C>T(p.Arg1885=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,614,042 control chromosomes in the GnomAD database, including 2,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 202 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2560 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.0630

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 2-26460909-G-A is Benign according to our data. Variant chr2-26460909-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26460909-G-A is described in Lovd as [Benign]. Variant chr2-26460909-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.063 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5655C>T	p.Arg1885=	synonymous_variant	44/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.3354C>T	p.Arg1118=	synonymous_variant	27/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5655C>T	p.Arg1885=	synonymous_variant	44/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.3354C>T	p.Arg1118=	synonymous_variant	27/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0456

AC:

6942

AN:

152160

Hom.:

202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.100

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0781

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.0648

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0624

Gnomad OTH

AF:

0.0651

GnomAD3 exomes

AF:

0.0458

AC:

11508

AN:

251370

Hom.:

318

AF XY:

0.0468

AC XY:

6366

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00880

Gnomad AMR exome

AF:

0.0292

Gnomad ASJ exome

AF:

0.0821

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0250

Gnomad FIN exome

AF:

0.0645

Gnomad NFE exome

AF:

0.0618

Gnomad OTH exome

AF:

0.0548

GnomAD4 exome

AF:

0.0562

AC:

82102

AN:

1461764

Hom.:

2560

Cov.:

AF XY:

0.0556

AC XY:

40449

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00917

Gnomad4 AMR exome

AF:

0.0314

Gnomad4 ASJ exome

AF:

0.0807

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0251

Gnomad4 FIN exome

AF:

0.0625

Gnomad4 NFE exome

AF:

0.0622

Gnomad4 OTH exome

AF:

0.0545

GnomAD4 genome

AF:

0.0456

AC:

6939

AN:

152278

Hom.:

202

Cov.:

AF XY:

0.0448

AC XY:

3339

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.0581

Gnomad4 ASJ

AF:

0.0781

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0238

Gnomad4 FIN

AF:

0.0648

Gnomad4 NFE

AF:

0.0625

Gnomad4 OTH

AF:

0.0644

Alfa

AF:

0.0571

Hom.:

154

Bravo

AF:

0.0443

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0642

EpiControl

AF:

0.0624

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 15, 2007	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.4

DANN

Benign

0.87

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