rs786201874
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.499_502del(p.Cys167GlnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
NF1
NM_001042492.3 frameshift
NM_001042492.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.72
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-31169905-CTGTT-C is Pathogenic according to our data. Variant chr17-31169905-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 185021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31169905-CTGTT-C is described in Lovd as [Pathogenic]. Variant chr17-31169905-CTGTT-C is described in Lovd as [Likely_pathogenic]. Variant chr17-31169905-CTGTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.499_502del | p.Cys167GlnfsTer10 | frameshift_variant | 5/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.499_502del | p.Cys167GlnfsTer10 | frameshift_variant | 5/57 | ||
NF1 | NM_001128147.3 | c.499_502del | p.Cys167GlnfsTer10 | frameshift_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.499_502del | p.Cys167GlnfsTer10 | frameshift_variant | 5/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251028Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135724
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GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442702Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 718206
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:12
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, flagged submission | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Nov 11, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 15, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Cys167Glnfs*10) 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 (rs786201874, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 10543400, 24294391). This variant is also known as 495delTGTT. ClinVar contains an entry for this variant (Variation ID: 185021). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 05, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: 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 reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000185021 / PMID: 10543400). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
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 | Medical Genetics, University of Parma | Dec 20, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 31, 2024 | This sequence change creates a premature translational stop signal (p.Cys167Glnfs*10) 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 (rs786201874, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (NF1) . This variant is associated with the following publications: (PMID: 18546366, 17726231, 17311297, 31533797, 24294391, 22155606, 12807981, 18041031, 10543400, 24676424, 20844836, 23913538, 30293248, 30530636, 28191890, 16835897, 24789688, 27838393, 28152038, 31730495, 30098238, 31370276, 34246755, 31066482).. This variant is also known as 495delTGTT. ClinVar contains an entry for this variant (Variation ID: 185021). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 08, 2013 | This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. In the published literature, the variant has been reported in individuals/families with neurofibromatosis 1 (NF1) or with clinical suspicion of NF1 (PMID: 34427956 (2022), 30530636 (2019), 27838393 (2017), 23913538 (2013), 17311297 (2007), 12807981 (2003), 10726756 (2000), 10543400 (1999)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2022 | Frameshift 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; Also known as c.495delTGTT; This variant is associated with the following publications: (PMID: 18546366, 17726231, 17311297, 31533797, 24294391, 22155606, 12807981, 18041031, 10543400, 24676424, 20844836, 23913538, 30293248, 30530636, 28191890, 16835897, 24789688, 27838393, 28152038, 31730495, 30098238, 31370276, 34246755, 31066482) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 26, 2021 | PVS1, PM6_Strong, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 11, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital | Nov 10, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2014 | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2021 | The c.499_502delTGTT variant, located in coding exon 5 of the NF1 gene, results from a deletion of 4 nucleotides at nucleotide positions 499 to 502, causing a translational frameshift with a predicted alternate stop codon (p.C167Qfs*10). This mutation has been observed in multiple patients with sporadic or familial NF1 (Osborn MJ and Upadhyaya M. Hum. Genet. 1999 Oct;105:327-32; Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Ars E et al. J. Med. Genet. 2003 Jun;40:e82; Schaefer IM et al. Int J Clin Exp Pathol, 2013 Nov;6:3003-8; Uusitalo E et al. Acta Derm. Venereol., 2014 Nov;94:663-6; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60; Giugliano T et al. Genes (Basel) 2019 07;10(8)). Of note, this mutation is also designated as c.495delTGTT and c.495_498del in published literature. 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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