rs13031859

Positions:

• chr2-26519093-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.244C>T​(p.Arg82Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,595,874 control chromosomes in the GnomAD database, including 166,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11813 hom., cov: 33)
  • Exomes 𝑓: 0.45 (154466 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0906329E-4).
• BP6: Variant 2-26519093-G-A is Benign according to our data. Variant chr2-26519093-G-A is described in ClinVar as [Benign]. Clinvar id is 21836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26519093-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.244C>T	p.Arg82Cys	missense_variant	4/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.244C>T	p.Arg82Cys	missense_variant	4/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.244C>T	p.Arg82Cys	missense_variant	4/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.244C>T	p.Arg82Cys	missense_variant	4/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54604 AN: 152024 Hom.: 11810 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.0815

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.428

GnomAD3 exomes AF: 0.404 AC: 93598 AN: 231612 Hom.: 20602 AF XY: 0.412 AC XY: 51568 AN XY: 125076

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.0898

Gnomad SAS exome AF: 0.405

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.474

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.453 AC: 653833 AN: 1443732 Hom.: 154466 Cov.: 35 AF XY: 0.452 AC XY: 324413 AN XY: 717318

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.456

Gnomad4 EAS exome AF: 0.0905

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.484

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.359 AC: 54617 AN: 152142 Hom.: 11813 Cov.: 33 AF XY: 0.355 AC XY: 26385 AN XY: 74378

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.455

Gnomad4 EAS AF: 0.0815

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.426

Alfa AF: 0.450 Hom.: 18681

Bravo AF: 0.362

TwinsUK AF: 0.498 AC: 1846

ALSPAC AF: 0.503 AC: 1938

ESP6500AA AF: 0.139 AC: 614

ESP6500EA AF: 0.485 AC: 4171

ExAC AF: 0.382 AC: 46128

Asia WGS AF: 0.225 AC: 787 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2019	The p.Arg82Cys variant in OTOF is classified as benign because it has been identified in 40% (104,089/262,952) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.00021	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.060
Sift	Benign	0.075	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0020	B;.
Vest4		0.34
MPC		0.21
ClinPred		0.021	T
GERP RS		1.2
Varity_R		0.079
gMVP		0.48

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: rs13031859; hg19: chr2-26741961; COSMIC: COSV55494794;