NM_001042492.3:c.1246C>T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.1246C>T(p.Arg416*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,778 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R416R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.1246C>T | p.Arg416* | stop_gained | Exon 11 of 58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.4 | c.1246C>T | p.Arg416* | stop_gained | Exon 11 of 57 | NP_000258.1 | ||
| NF1 | NM_001128147.3 | c.1246C>T | p.Arg416* | stop_gained | Exon 11 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000400 AC: 1AN: 250118 AF XY: 0.00000739 show subpopulations
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459778Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726270 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:12
Variant summary: NF1 c.1246C>T (p.Arg416X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250118 control chromosomes. c.1246C>T has been widely reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (example, Osborne_1999, Fahsold_2000, Sabbagh_2013). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Arg416*) 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 present in population databases (rs764079291, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 10543400, 10712197, 15060124, 23668869, 25325900). ClinVar contains an entry for this variant (Variation ID: 404597). For these reasons, this variant has been classified as Pathogenic. -
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An NF1 c.1246C>T (p.Arg416*) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals with neurofibromatosis type 1 (Osborn MJ et al., PMID: 10543400; Fahsold R et al., PMID: 10712197; Mattocks C et al., PMID: 15060124; Ko JM et al., PMID:23668869; Maruoka R et al., PMID: 25325900; Duat Rodriguez A et al., PMID: 25541118; Laycock-van Spyk S et al., PMID: 22155606). It is only observed on 1/1,611,594 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. It has been reported in the ClinVar database as pathogenic by several submitters (ClinVar variation ID: 404597). The NF1 c.1246C>T (p.Arg416*) variant causes a premature termination codon, which is predicted to result in protein truncation or lead to nonsense mediated decay. Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation (Leon-Quintero FZ et al., PMID: 39434542), this variant is classified as pathogenic. -
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ACMG classification criteria: PVS1 very strong, PS4, PM2 moderate -
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The stop gained c.1246C>T (p.Arg416Ter) variant in the NF1 gene has been been reported as a recurring pathogenic variant in several individuals affected with Neurofibromatosis Type 1 (Fahsold, R et al., 2000; Maruoka, Ryo et al.,2014). This variant is reported with the allele frequency 0.0003% in the gnomAD. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.1246C>T in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:6
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with neurofibromatosis type 1. -
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The NF1 c.1246C>T; p.Arg416Ter variant (rs764079291) has been reported in several unrelated individuals affected with neurofibromatosis type 1 (Fahsold 2000, Ko 2013, Maruoka 2014, Osborn 1999, Xu 2014). It is also reported in ClinVar (Variation ID: 404597). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. 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, this variant is considered to be pathogenic. References: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. PMID: 10712197. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. PMID: 23668869 Maruoka R et al. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014 Nov;18(11):722-35. PMID: 25325900. Osborn MJ et al. Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations. Hum Genet. 1999 Oct;105(4):327-32. PubMed: 10543400. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. PMID: 24789688. -
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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 (gnomAD); This variant is associated with the following publications: (PMID: 25541118, 29922827, 25525159, 22155606, 29185159, 23244495, 25325900, 15060124, 23668869, 26969325, 29082380, 10712197, 29290338, 10543400, 24789688, 31370276, 30530636, 30290804, 29914388, 29489754, 27535533) -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:2
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PM2+PS4_Moderate+PVS1 -
Neurofibromatosis-Noonan syndrome Pathogenic:2
This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PS2;PVS1 -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23668869, 25325900, 29290338, 31370276). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000404597 /PMID: 10543400). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The p.R416* pathogenic mutation (also known as c.1246C>T), located in coding exon 11 of the NF1 gene, results from a C to T substitution at nucleotide position 1246. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been identified in numerous individuals with clinical diagnoses of neurofibromatosis type 1 (NF1) (Osborn MJ et al. Hum. Genet. 1999 Oct;105:327-32; Ko JM et al. Pediatr. Neurol. 2013 Jun;48:447-53; Maruoka R et al. Genet. Test Mol. Biomarkers. 2014 Nov;18:722-35; Hutter S et al. Hum. Genet. 2016 May;135:469-75; Mao B et al. BMC Med Genet, 2018 06;19:101; Melloni G et al. Cancers (Basel), 2019 11;11:; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Giugliano T et al. Genes (Basel), 2019 07;10:). 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