rs1064794273
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.801G>A(p.Trp267Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.801G>A | p.Trp267Ter | stop_gained | 8/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.801G>A | p.Trp267Ter | stop_gained | 8/57 | ||
NF1 | NM_001128147.3 | c.801G>A | p.Trp267Ter | stop_gained | 8/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.801G>A | p.Trp267Ter | stop_gained | 8/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461718Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727158
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jul 25, 2023 | An NF1 c.801G>A (p.Trp267Ter) variant was identified at an allelic fraction consistent with somatic origin. This variant has been previously reported in at least five individuals affected with neurofibromatosis type 1 (Gasparini P et al., PMID: 8834249; Fahsold R et al., PMID: 10712197; Wiest V et al., PMID: 14635100). The NF1 c.801G>A (p.Trp267Ter) variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar Variation ID: 420075), and it has been reported in four cases in the cancer database COSMIC. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The NF1 c.801G>A (p.Trp267Ter) variant introduces a premature termination codon, resulting in a transcript that is predicted to undergo nonsense-mediated decay. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the NF1 c.801G>A (p.Trp267Ter) variant is classified as pathogenic.Of note, this assay cannot determine if the two pathogenic NF1 variants identified in this patient are in cis or in trans. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2023 | ClinVar contains an entry for this variant (Variation ID: 420075). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 8834249, 10712197, 14635100). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp267*) 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). For these reasons, this variant has been classified as Pathogenic. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2018 | The NF1 c.801G>A; p.Trp267Ter variant is reported in the literature in multiple patients with neurofibromatosis 1 (Gasparini 1996, Fahsold 2000, Wiest 2003, Maertens 2006, Laycock-van Spyk 2011, Sabbagh 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The p.Trp267Ter variant is listed in ClinVar (ClinVar ID 420075). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Trp267Ter variant is considered to be pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2021 | 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 10712197, 8834249, 23913538, 31730495) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 09, 2018 | The p.W267* pathogenic mutation (also known as c.801G>A), located in coding exon 8 of the NF1 gene, results from a G to A substitution at nucleotide position 801. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation has been reported in multiple individuals with neurofibromatosis type 1 (Gasparini P et al. Hum. Genet., 1996 Apr;97:492-5; Wiest V et al. Hum. Mutat., 2003 Dec;22:423-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at