rs1131691096
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.1721+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001042492.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1721+1G>A | splice_donor_variant | ENST00000358273.9 | |||
NF1 | NM_000267.3 | c.1721+1G>A | splice_donor_variant | ||||
NF1 | NM_001128147.3 | c.1722G>A | p.Arg574= | synonymous_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1721+1G>A | splice_donor_variant | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change affects a donor splice site in intron 15 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 18546366, 23913538). ClinVar contains an entry for this variant (Variation ID: 457545). Studies have shown that disruption of this splice site results in skipping of exon 15, also known as exon 11 and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 01, 2023 | PVS1, PS4_Moderate, PM2 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2022 | Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Pros 2008, Sabbagh 2013); Observed in individuals with suspected or clinically diagnosed neurofibromatosis type 1 referred for genetic testing at GeneDx and in the published literature (Pros 2008, Sabbagh 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18546366, 25525159, 23913538) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 21, 2024 | The c.1721+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 15 of the NF1 gene. This variant was identified in 1 of 565 unrelated French probands with clinical diagnoses or suspicion of NF1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8). In addition, this alteration was identified in another cohort of 374 patients undergoing genetic testing due to a diagnosis or clinical suspicion of neurofibromatosis type 1 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at