rs876657715
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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.6854dupA(p.Tyr2285fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,080 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: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NF1
NM_001042492.3 frameshift, stop_gained
NM_001042492.3 frameshift, stop_gained
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.62
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 17-31338737-T-TA is Pathogenic according to our data. Variant chr17-31338737-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 228382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.6854dupA | p.Tyr2285fs | frameshift_variant, stop_gained | 46/58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.6791dupA | p.Tyr2264fs | frameshift_variant, stop_gained | 45/57 | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.6854dupA | p.Tyr2285fs | frameshift_variant, stop_gained | 46/58 | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152160Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461080Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726886
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GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | The p.Tyr2285X variant in NF1 has been reported in >10 individuals with Neurofib romatosis I (NF1) (Upadhyaya 1996, Leiden Open Variation Database), 3 of which w ere apparently de novo. It was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsen se variant leads to a premature termination codon at position 2285, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss-of-function o f the NF1 gene is an established disease mechanism in NF1. In summary, this vari ant meets our criteria to be classified as pathogenic for NF1 in an autosomal do minant manner. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 13, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Tyr2264*) 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 individuals with neurofibromatosis type 1 (PMID: 8837715, 16941471, 17311297, 23913538, 24232412, 25325900, 27838393). This variant is also known as p.Tyr2285*. ClinVar contains an entry for this variant (Variation ID: 228382). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2022 | 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 (gnomAD); This variant is associated with the following publications: (PMID: 31370276, 10494088, 27322474, 27838393, 8837715, 15146469, 29566708, 29618358, 24232412, 16941471, 29914388, 30308447, 31533797, 32107864, 25325900, 31776437) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 08, 2021 | The NF1 c.6854dupA;p.Tyr2285Ter variant (also known as c.6791dupA;p.Tyr2264Ter) is published in the medical literature in several individuals with a clinical diagnosis of neurofibromatosis type 1 (De Luca 2004, Maruoka 2014, Upadhyaya 1996). The variant is listed in the ClinVar database (Variation ID: 228382), but not in the dbSNP variant database or in the general population-based databases (Exome Variant Server, Genome Aggregation Database). This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as pathogenic. References: De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. 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. Upadhyaya M et al. Characterization of six mutations in exon 37 of neurofibromatosis type 1 gene. Am J Med Genet. 1996 Jul 26;67(4):421-3. - |
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 | - - |
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
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PS4_Supporting+PP4 - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2024 | The c.6791dupA pathogenic mutation, located in coding exon 45 of the NF1 gene, results from a duplication of A at nucleotide position 6791, causing a translational frameshift with a predicted alternate stop codon (p.Y2264*). This alteration has been reported in multiple unrelated individuals with neurofibromatosis type 1 (Upadhyaya M et al. Am J Med Genet, 1996 Jul;67:421-3; Pros E et al. Hum Mutat, 2006 Nov;27:1104-14; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Mao B et al. BMC Med Genet, 2018 06;19:101; Melloni G et al. Cancers (Basel), 2019 Nov;11; Zhu G et al. Orphanet J Rare Dis, 2019 Sep;14:221; Giugliano T et al. Genes (Basel), 2019 Jul;10:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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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Details are displayed if max score is > 0.2
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