rs80356569

Positions:

• chr2-26477505-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.2317C>T​(p.Arg773Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,602,582 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.014 (227 hom.)
• Consequence: OTOF NM_194248.3 missense, splice_region
• Scores: Splicing: ADA: 0.8316
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 7.79

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=0.0074848533).
• BP6: Variant 2-26477505-G-A is Benign according to our data. Variant chr2-26477505-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477505-G-A is described in Lovd as [Benign]. Variant chr2-26477505-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	20/47	ENST00000272371.7
OTOF	NM_194323.3	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	3/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2317C>T	p.Arg773Cys	missense_variant, splice_region_variant	20/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.76C>T	p.Arg26Cys	missense_variant, splice_region_variant	3/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2377 AN: 152128 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0154 AC: 3504 AN: 227648 Hom.: 40 AF XY: 0.0158 AC XY: 1951 AN XY: 123548

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0139 AC: 20232 AN: 1450336 Hom.: 227 Cov.: 33 AF XY: 0.0144 AC XY: 10352 AN XY: 720362

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.0541

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.000782

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0156 AC: 2377 AN: 152246 Hom.: 30 Cov.: 32 AF XY: 0.0153 AC XY: 1140 AN XY: 74452

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0160 Hom.: 34

Bravo AF: 0.0174

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.0210 AC: 91

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.0145 AC: 1746

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2018	This variant is associated with the following publications: (PMID: 22607986, 12114484, 16371502, 19461658) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2009	- -
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:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
MetaRNN	Benign	0.0075	T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D;D;.;D;D;.
Sift4G	Uncertain	0.031	D;D;.;D;D;.
Polyphen		0.17	B;D;.;D;.;D
Vest4		0.73
MPC		0.49
ClinPred		0.029	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Pathogenic	0.78
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: rs80356569; hg19: chr2-26700373; COSMIC: COSV55507243; COSMIC: COSV55507243;