rs1329683225
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.7869+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.7869+1G>A | splice_donor_variant, intron_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.7806+1G>A | splice_donor_variant, intron_variant | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.7869+1G>A | splice_donor_variant, intron_variant | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250648Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135552
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461000Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726828
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 22, 2022 | This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 480091). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 11857752, 26056819). This sequence change affects a donor splice site in intron 52 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2024 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26056819, 29415745, 11857752, 12807981, 18546366, 31766501, 34953813) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2016 | Thec.7869+1G>Aintronicpathogenic mutation results from a G to A substitution one nucleotide after codingexon53 of theNF1gene. This nucleotide position is highly conserved in available vertebrate species. This mutation, designated as c.7806+1G>A,has been identified in a female with neurofibromatosis type 1 (NF1) and also in her affected father (Zhang J et al,Sci Rep2015; 5:11291). This nucleotide position is highly conserved in available vertebrate species and,using theBDGPandESEfindersplice site prediction tools, the c.7869+1G>Aalterationis predicted to abolish the native splice donor site.Other nucleotide substitutions at this position (also known as c.7806+1 andIVS44+1) have beenidentifiedinsuspected-NF1cohorts and shown to causeexonskipping at themRNAlevel(Ars E et al,J. Med. Genet. 2003 Jun; 40(6):e82;ProsE et al,Hum.Mutat. 2008 Sep; 29(9):E173-93).In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at