rs1555613843
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.2251+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001042492.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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PM2_Supporting+PVS1+PS4_Supporting+PP4 -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The c.2251+1G>A pathogenic intronic mutation results from a G to A substitution one nucleotide after coding exon 18 of the NF1 gene. This alteration has been reported in individuals with a clinical diagnosis of neurofibromatosis type 1 (Origone P et al. Hum Mutat, 2003 Aug;22:179-80; Assunto A et al. Orphanet J Rare Dis, 2019 11;14:261; Ambry internal data). 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 and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at