rs876660696
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.5991G>A(p.Trp1997*) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 stop_gained
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.: 29
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Trp1976*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of neurofibromatosis, type 1 (PMID: 30014477, 31370276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 233869). For these reasons, this variant has been classified as Pathogenic. -
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Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1
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not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30014477, 22108604, 32486389, 22155606, 31370276, 31730495) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.W1997* pathogenic mutation (also known as c.5991G>A), located in coding exon 40 of the NF1 gene, results from a G to A substitution at nucleotide position 5991. This changes the amino acid from a tryptophan to a stop codon within coding exon 40. This variant has been seen as somatic mutation in a tumor from one patient with neurofibromatosis with a germline NF1 microdeletion and one patient with a reportedly sporadic pheochromocytoma (Laycock-van Spyk S et al. Hum. Genomics 2011 Oct; 5(6):623-90; Thomas L et al. Eur. J. Hum. Genet. 2012 Apr; 20(4):411-9; Welander J et al.J. Clin. Endocrinol. Metab. 2014 Jul; 99(7):E1352-60; Stenman A et al. Endocr. Pathol. 2015 Mar; 26(1):9-14). In addition to the data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations 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