2-26474612-C-T

Position:

chr2-26474612-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_194248.3(OTOF):c.3189G>A(p.Ala1063=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,148 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 31)

Exomes 𝑓: 0.020 ( 355 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: -3.09

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 2-26474612-C-T is Benign according to our data. Variant chr2-26474612-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21843.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, not_provided=1}.

BP7

Synonymous conserved (PhyloP=-3.09 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2279/152272) while in subpopulation NFE AF= 0.0195 (1327/68018). AF 95% confidence interval is 0.0186. There are 19 homozygotes in gnomad4. There are 1029 alleles in male gnomad4 subpopulation. Median coverage is 31. 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	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.3189G>A	p.Ala1063=	synonymous_variant	26/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.948G>A	p.Ala316=	synonymous_variant	9/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.3189G>A	p.Ala1063=	synonymous_variant	26/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.948G>A	p.Ala316=	synonymous_variant	9/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2276

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0145

AC:

3639

AN:

250580

Hom.:

AF XY:

0.0148

AC XY:

2006

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0195

AC:

28520

AN:

1460876

Hom.:

355

Cov.:

AF XY:

0.0190

AC XY:

13795

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.00789

Gnomad4 ASJ exome

AF:

0.0179

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.0227

Gnomad4 NFE exome

AF:

0.0223

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0150

AC:

2279

AN:

152272

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1029

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0199

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0147

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0222

EpiControl

AF:

0.0212

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2018	This variant is associated with the following publications: (PMID: 16371502, 18381613, 20301429) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:1Other:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 18, 2010

Ala1063Ala in exon 26 of OTOF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP with a frequency of 1/118 (.8%) in the YRI West African population (rs116649108), is reported as benign in two publication (Varga 2006, Rodriguez-Ballesteros 2008) and has been identified in 5/211 (2.4%) probands tested by our laboratory (at least 2 have Usher syndrome). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.6

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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