rs111033427

Positions:

• chr2-26477768-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000402415.8(OTOF):​c.-46C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,612,286 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (33 hom.)
• Consequence: OTOF ENST00000402415.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.408

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26477768-G-C is Benign according to our data. Variant chr2-26477768-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 48188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477768-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2215-19C>G		intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.-27-19C>G		intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2215-19C>G		intron_variant		1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.-27-19C>G		intron_variant		1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00437 AC: 1084 AN: 248176 Hom.: 9 AF XY: 0.00449 AC XY: 606 AN XY: 134820

Gnomad AFR exome AF: 0.000883

Gnomad AMR exome AF: 0.00706

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000886

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00536 AC: 7825 AN: 1460028 Hom.: 33 Cov.: 34 AF XY: 0.00529 AC XY: 3841 AN XY: 726292

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000731

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.00623

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74428

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00513 Hom.: 0

Bravo AF: 0.00438

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00749

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOF: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2013	p.Thr42Thr in exon 1A of OTOF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.7% (57/8531) of Eur opean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs111033427). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2015	- -

OTOF-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.45

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

Other links and lift over

dbSNP: rs111033427; hg19: chr2-26700636;