rs61747275

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_194248.3(OTOF):c.5391C>T(p.Phe1797=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,154 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 36 hom., cov: 32)

Exomes 𝑓: 0.010 ( 241 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.0640

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=-0.42).

BP6

Variant 2-26461838-G-A is Benign according to our data. Variant chr2-26461838-G-A is described in ClinVar as [Benign]. Clinvar id is 21857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26461838-G-A is described in Lovd as [Likely_benign]. Variant chr2-26461838-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.064 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0169 (2567/152266) while in subpopulation AFR AF= 0.0369 (1534/41538). AF 95% confidence interval is 0.0354. There are 36 homozygotes in gnomad4. There are 1256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5391C>T	p.Phe1797=	synonymous_variant	43/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.3090C>T	p.Phe1030=	synonymous_variant	26/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5391C>T	p.Phe1797=	synonymous_variant	43/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.3090C>T	p.Phe1030=	synonymous_variant	26/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2561

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0369

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0314

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00741

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0150

AC:

3760

AN:

251488

Hom.:

AF XY:

0.0163

AC XY:

2218

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.00786

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0430

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00882

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0100

AC:

14678

AN:

1461888

Hom.:

241

Cov.:

AF XY:

0.0112

AC XY:

8161

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0363

Gnomad4 AMR exome

AF:

0.00850

Gnomad4 ASJ exome

AF:

0.0420

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0427

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00637

Gnomad4 OTH exome

AF:

0.0152

GnomAD4 genome

AF:

0.0169

AC:

2567

AN:

152266

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1256

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0369

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.0328

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0317

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00741

Gnomad4 OTH

AF:

0.0228

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.0186

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.5

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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