rs143141993

Positions:

• chr2-26477829-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000272371.7(OTOF):​c.2215-80T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,581,032 control chromosomes in the GnomAD database, including 15 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 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (13 hom.)
• Consequence: OTOF ENST00000272371.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.777

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074367225).
• BP6: Variant 2-26477829-A-G is Benign according to our data. Variant chr2-26477829-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48189.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=4}. Variant chr2-26477829-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2215-80T>C		intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.-28+15T>C		intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2215-80T>C		intron_variant		1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.-28+15T>C		intron_variant		1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00267 AC: 519 AN: 194268 Hom.: 2 AF XY: 0.00249 AC XY: 260 AN XY: 104290

Gnomad AFR exome AF: 0.000955

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000770

Gnomad FIN exome AF: 0.000158

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00397 AC: 5675 AN: 1428770 Hom.: 13 Cov.: 34 AF XY: 0.00385 AC XY: 2728 AN XY: 707892

Gnomad4 AFR exome AF: 0.000614

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00121

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000133

Gnomad4 FIN exome AF: 0.000179

Gnomad4 NFE exome AF: 0.00477

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74456

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00411 Hom.: 3

Bravo AF: 0.00347

ExAC AF: 0.00212 AC: 251

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOF: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2016	p.Leu22Pro in exon 1A of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (130/28336) of European chromos omes by the Exome Aggregation Consortium (http://exac.broadinstitute.org/; dbSNP rs143141993). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

OTOF-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2022

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_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.66
DANN	Uncertain	0.99
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N
Polyphen		0.020	B
ClinPred		0.037	T
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143141993; hg19: chr2-26700697; COSMIC: COSV55506434; COSMIC: COSV55506434;