rs1555605409
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001042492.3(NF1):c.288+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001042492.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.288+5G>A | splice_region_variant, intron_variant | Intron 3 of 57 | ENST00000358273.9 | NP_001035957.1 | ||
NF1 | NM_000267.3 | c.288+5G>A | splice_region_variant, intron_variant | Intron 3 of 56 | NP_000258.1 | |||
NF1 | NM_001128147.3 | c.288+5G>A | splice_region_variant, intron_variant | Intron 3 of 14 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 25
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
This sequence change falls in intron 3 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 27999334, 29618358; internal data). ClinVar contains an entry for this variant (Variation ID: 642764). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.288+5G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12624144, 22617876). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
This variant has been reported in individuals with Neurofibromatosis type 1 (NF1) in the published literature (PMIDs: 27999334 (2016) and 29618358 (2018)). A different variant located at the same nucleotide position (NF1 c.288+5G>C) has been shown to result in aberrant NF1 splicing and exon 3 skipping and reported to be deleterious (PMID: 12624144 (2003), 22617876 (20012), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/)). Therefore, the variant is classified as likely pathogenic. -
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22617876, 17576681, 12624144, 9536098, 31766501, 29618358, 27999334, 31776437) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The c.288+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the NF1 gene. This alteration was identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Cunha KS et al. Genes (Basel), 2016 Dec;7:; Corsello G et al. Ital J Pediatr, 2018 Apr;44:45). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at