rs80356578

Positions:

• chr2-26465704-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.4767C>T​(p.Arg1589=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,250 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (95 hom., cov: 33)
  • Exomes 𝑓: 0.011 (569 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -2.18

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-26465704-G-A is Benign according to our data. Variant chr2-26465704-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26465704-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4767C>T	p.Arg1589=	synonymous_variant	38/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2466C>T	p.Arg822=	synonymous_variant	21/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4767C>T	p.Arg1589=	synonymous_variant	38/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.2466C>T	p.Arg822=	synonymous_variant	21/29	1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2377 AN: 152250 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0301 AC: 7569 AN: 251462 Hom.: 402 AF XY: 0.0250 AC XY: 3399 AN XY: 135922

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0402

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.0872

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0107 AC: 15583 AN: 1461882 Hom.: 569 Cov.: 32 AF XY: 0.00986 AC XY: 7172 AN XY: 727246

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.00341

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.00354

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0156 AC: 2379 AN: 152368 Hom.: 95 Cov.: 33 AF XY: 0.0194 AC XY: 1445 AN XY: 74506

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0424

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0901

Gnomad4 NFE AF: 0.00539

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00674 Hom.: 9

Bravo AF: 0.0142

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2010	This variant is not expected to have clinical significance because it does not a lter an amino acid residue, is not located near a splice junction, and is report ed as a benign polymorphism (Varga 2006, Smith 2008). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 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:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-0.71
CADD	Benign	0.011
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs80356578; hg19: chr2-26688572; COSMIC: COSV55514045;