rs55639868

Positions:

• chr2-26502290-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.710+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,840 control chromosomes in the GnomAD database, including 94 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 0.0088 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (87 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -1.39

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-26502290-G-A is Benign according to our data. Variant chr2-26502290-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48273.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}. Variant chr2-26502290-G-A is described in Lovd as [Likely_benign]. Variant chr2-26502290-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00884 (1347/152306) while in subpopulation NFE AF= 0.0136 (928/68018). AF 95% confidence interval is 0.0129. There are 7 homozygotes in gnomad4. There are 634 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.710+10C>T		intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.710+10C>T		intron_variant			NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.710+10C>T		intron_variant		1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000403946.7	c.710+10C>T		intron_variant		5		ENSP00000385255	P4

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1348 AN: 152188 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00999 AC: 2506 AN: 250932 Hom.: 17 AF XY: 0.0102 AC XY: 1388 AN XY: 135666

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.00303

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0102 AC: 14939 AN: 1461534 Hom.: 87 Cov.: 32 AF XY: 0.0104 AC XY: 7528 AN XY: 727076

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00435

Gnomad4 FIN exome AF: 0.00396

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00884 AC: 1347 AN: 152306 Hom.: 7 Cov.: 33 AF XY: 0.00851 AC XY: 634 AN XY: 74464

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00842

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2012	710+10C>T in exon 7 of OTOF: This variant is not expected to have clinical signi ficance because it is not located within the splice consensus sequence, has been identified in 1.4% (96/7020) of European American chromosomes and 0.2% (8/3738) of African American chromosomes in a broad population by the NHLBI Exome sequen cing project (http://evs.gs.washington.edu/EVS/; dbSNP rs55639868). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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	Athena Diagnostics	Feb 27, 2019	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.9
DANN	Benign	0.59

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: rs55639868; hg19: chr2-26725158;