rs201745796

Variant names:

• chr2-26477167-C-T
• rs201745796
• NM_194248.3:c.2523+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_194248.3(OTOF):​c.2523+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,608,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: OTOF NM_194248.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-26477167-C-T is Benign according to our data. Variant chr2-26477167-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48201.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2523+5G>A		splice_region_variant, intron_variant	Intron 21 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.282+5G>A		splice_region_variant, intron_variant	Intron 4 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2523+5G>A		splice_region_variant, intron_variant	Intron 21 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.282+5G>A		splice_region_variant, intron_variant	Intron 4 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000244 AC: 59 AN: 242192 AF XY: 0.000264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00306

Gnomad EAS exome AF: 0.000221

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1456352 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 107 AN XY: 724504

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000673 AC: 3 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00342 AC: 89 AN: 26052

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39672

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50378

Middle Eastern (MID) AF: 0.000715 AC: 4 AN: 5594

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1110604

Other (OTH) AF: 0.000365 AC: 22 AN: 60244

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.000164

EpiControl AF: 0.000536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Oct 05, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2523+5G>A variant in OTOF has not been reported in the literature nor previo usly identified by our laboratory. The 2523+5G>A variant is located in the 5' sp lice region but does not affect the invariant +1 and +2 positions. However, posi tions +3 to +6 are part of the splicing consensus sequence and variants involvin g these positions sometimes affect splicing. It should be noted that this lab ha s only sequenced the OTOF gene in 9 Ashkenazi Jewish individuals and no Ashkenaz i Jewish healthy controls. In addition, healthy control information is limited i n either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this population. Future analysi s could reveal that the 2523+5G>A variant is common in this population and there fore unlikely to be pathogenic. In the absence of additional information, such a s control data, segregation studies or functional analysis, the clinical signifi cance of this variant cannot be determined at this time. -

Dec 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTOF c.2523+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 242192 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00024 vs 0.0011), allowing no conclusion about variant significance. c.2523+5G>A has been reported in the literature in individuals affected with hearing loss (Liu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35114279). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

OTOF-related disorder Benign:1

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

not provided Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	21
DANN	Benign	0.33
PhyloP100		1.9
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201745796; hg19: chr2-26700035;