rs41286009

chr2-26465040-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_194248.3(OTOF):c.4800-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,463,404 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 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: OTOF NM_194248.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002085
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.191

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-26465040-G-A is Benign according to our data. Variant chr2-26465040-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178505.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=2}. Variant chr2-26465040-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4800-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000272371.7
OTOF	NM_194323.3	c.2499-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4800-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2499-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00184 AC: 291 AN: 158126 Hom.: 1 AF XY: 0.00189 AC XY: 158 AN XY: 83748

Gnomad AFR exome AF: 0.000245

Gnomad AMR exome AF: 0.000577

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000779

Gnomad SAS exome AF: 0.00286

Gnomad FIN exome AF: 0.000585

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00267 AC: 3507 AN: 1311198 Hom.: 8 Cov.: 31 AF XY: 0.00273 AC XY: 1743 AN XY: 638610

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00274

Gnomad4 FIN exome AF: 0.000555

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74408

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00169

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2020	- -

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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

4800-11C>T in Intron 38 of OTOF: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (23/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41286009). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.3
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs41286009; hg19: chr2-26687908;