rs55886964

Positions:

chr2-26495076-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.766-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,976 control chromosomes in the GnomAD database, including 1,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 64 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1056 hom. )

Consequence

OTOF
NM_194248.3 splice_region, intron

Scores

Splicing: ADA: 0.0002061

Clinical Significance

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

Conservation

PhyloP100: 3.41

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 (BayesDel_noAF=-0.5).

BP6

Variant 2-26495076-G-A is Benign according to our data. Variant chr2-26495076-G-A is described in ClinVar as [Benign]. Clinvar id is 48274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26495076-G-A is described in Lovd as [Benign]. Variant chr2-26495076-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0259 (3943/152246) while in subpopulation SAS AF= 0.0435 (210/4830). AF 95% confidence interval is 0.0387. There are 64 homozygotes in gnomad4. There are 1953 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.766-3C>T		splice_region_variant, intron_variant		ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.766-3C>T		splice_region_variant, intron_variant			NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.766-3C>T		splice_region_variant, intron_variant		1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.766-3C>T		splice_region_variant, intron_variant		5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3941

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00613

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0428

Gnomad FIN

AF:

0.0522

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0370

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0313

AC:

7842

AN:

250788

Hom.:

190

AF XY:

0.0339

AC XY:

4593

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00536

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0280

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0493

Gnomad FIN exome

AF:

0.0551

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0330

GnomAD4 exome

AF:

0.0349

AC:

51026

AN:

1461730

Hom.:

1056

Cov.:

AF XY:

0.0357

AC XY:

25978

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00436

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.0272

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0507

Gnomad4 FIN exome

AF:

0.0553

Gnomad4 NFE exome

AF:

0.0363

Gnomad4 OTH exome

AF:

0.0310

GnomAD4 genome

AF:

0.0259

AC:

3943

AN:

152246

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1953

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00611

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.0435

Gnomad4 FIN

AF:

0.0522

Gnomad4 NFE

AF:

0.0370

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0321

Hom.:

Bravo

AF:

0.0215

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0352

EpiControl

AF:

0.0330

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

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

-0.50

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.0040

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