rs142333075

chr2-26558521-G-Achr2-26558521-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_194248.3(OTOF):c.51C>T(p.Gly17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,613,968 control chromosomes in the GnomAD database, including 8 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 0.0025 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.401

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-26558521-G-A is Benign according to our data. Variant chr2-26558521-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48257.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.51C>T	p.Gly17=	synonymous_variant	1/47	ENST00000272371.7
OTOF	NM_001287489.2	c.51C>T	p.Gly17=	synonymous_variant	1/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.51C>T	p.Gly17=	synonymous_variant	1/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.51C>T	p.Gly17=	synonymous_variant	1/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152102 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251176 Hom.: 3 AF XY: 0.000479 AC XY: 65 AN XY: 135802

Gnomad AFR exome AF: 0.00832

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1461748 Hom.: 3 Cov.: 31 AF XY: 0.000287 AC XY: 209 AN XY: 727192

Gnomad4 AFR exome AF: 0.00881

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152220 Hom.: 5 Cov.: 31 AF XY: 0.00234 AC XY: 174 AN XY: 74414

Gnomad4 AFR AF: 0.00833

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.00281

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	This variant is associated with the following publications: (PMID: 19461658) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Gly17Gly in Exon 01 of OTOF: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 0.5% (17/3738) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs142333075). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain: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. -

OTOF-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2021

This variant is classified as 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	-0.61
Cadd	Benign	6.6
Dann	Benign	0.86

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: rs142333075; hg19: chr2-26781389; COSMIC: COSV55504679; COSMIC: COSV55504679;