rs786201915
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.6855C>A(p.Tyr2285Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,200 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NF1
NM_001042492.3 stop_gained
NM_001042492.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 2.69
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 17-31338739-C-A is Pathogenic according to our data. Variant chr17-31338739-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 185082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31338739-C-A is described in Lovd as [Pathogenic]. Variant chr17-31338739-C-A is described in Lovd as [Pathogenic]. Variant chr17-31338739-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.6855C>A | p.Tyr2285Ter | stop_gained | 46/58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.3 | c.6792C>A | p.Tyr2264Ter | stop_gained | 45/57 | NP_000258.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | c.6855C>A | p.Tyr2285Ter | stop_gained | 46/58 | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461050Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726870
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GnomAD4 genome 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:27
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 23, 2021 | The inherited heterozygous nonsense variant c.6855C>A, p.Tyr2285Ter identified in NF1 has been reported in individuals affected with NF1-related disorders (PMID:7607663, 9385374, 10607834, 12807981, 17311297, 26962827). The variant has one heterozygous in gnomAD v3.1.1 database indicating it is an extremely rare allele in the populations represented in this database. This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. Loss of function variants in NF1 are known to be pathogenic. Based on the available evidence, the inherited c.6855C>A, p.Tyr2285Ter variant in the NF1 gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | May 25, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (PMID: 20301288). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant associated with neurofibromatosis type 1 (ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (external report). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is 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: VCV000185082/PMID:7607663/3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Dec 20, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Feb 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Tyr2264*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. 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: 7607663, 9385374, 10607834, 12807981, 17311297, 26962827). ClinVar contains an entry for this variant (Variation ID: 185082). Studies have shown that this premature translational stop signal results in skipping of exon 45, but is expected to preserve the integrity of the reading-frame (PMID: 9385374, 10607834, 16870183, 22925204; Invitae). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2020 | Variant summary: NF1 c.6792C>A (p.Tyr2264X) 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. In addition, multiple functional studies report experimental evidence that this variant affects mRNA splicing and results in exon 45 skipping (Hoffmeyer_1998, Ars_2000, Baralle_2006). The variant was absent in 251198 control chromosomes (gnomAD). c.6792C>A has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 and cosegregated with the disease phenotype in families (Robinson_1995, Hoffmeyer_1998, Ars_2000, Assunto_2019). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 26, 2021 | The NF1 c.6855C>A variant is classified as Pathogenic (PVS1, PS4_Moderate, PS3, PM2, PP4) Also known as(NM_000267.3):c.6792C>G;p.(Tyr2264*) in exon 37 - |
| 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 | MGZ Medical Genetics Center | Aug 09, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 15, 2024 | PVS1, PS4, PS1, PM2, PM6 - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 03, 2017 | The NF1 c.6792C>A (p.Tyr2264*, also known Y2264X) variant creates a premature stop codon in the NF1 gene. RNA studies have shown this variant does not trigger nonsense-mediated decay, but causes the in-frame skipping of exon 45 (also known as exon 37, c.2253_2286) in the NF1 gene (PMIDs: 22925204 (2013), 9463322 (1998), 9385374 (1997)). This variant has been reported in multiple individuals/families with neurofibromatosis type 1 (PMIDs: 30530636 (2019), 31347283 (2019), 31730495 (2019), 30290804 (2018), 26962827 (2016), 27322474 (2016), 23668869 (2013), 23913538 (2013), 17311297 (2007), 16479075 (2006), 15060124 (2004), 12807981 (2003), 12112660 (2002), 10607834 (2000)), including one de novo case (PMID: 27838393 (2017)). The frequency of this variant in the general population, 0.000007 (1/152150 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay, with some studies showing skipping of exon 37 in 20-30% of transcripts (Wimmer 2007, Hernandez-Imaz 2013); Observed de novo with and without confirmed parentage in multiple unrelated patients with neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Cali 2017); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31370276, 30530636, 28152038, 7607663, 27074763, 31730495, 32582540, 10494088, 17311297, 23913538, 25525159, 26962827, 27838393, 22925204, 30290804, 31766501, 31347283, 31645347, 31776437, 32623769, 33469372, 33911094, 34273915, 34080803, Kirat[article]) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 04, 2022 | PP1_strong, PM2, PS2, PS4_moderate, PVS1_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 14, 2023 | The NF1 c.6855C>A; p.Tyr2285Ter variant (rs772295894), also known as c.6792C>A; p.Tyr2264Ter for NM_000267, is described as a recurrent variant associated with neurofibromatosis type 1 and studies have also shown it to cause exon skipping (Buske 1999, Hernandez-Imaz 2013, Robinson 1995, Sabbagh 2013, Wimmer 2007, Zhu 2016). This variant is also reported in ClinVar (Variation ID: 185082). It is absent from 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: Buske A et al. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999 Oct 8;86(4):328-30. PMID: 10494088 Hernandez-Imaz E et al. Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1. Clin Genet. 2013 May;83(5):462-6. PMID: 22925204 Robinson PN et al. Two recurrent nonsense mutations and a 4 bp deletion in a quasi-symmetric element in exon 37 of the NF1 gene. Hum Genet. 1995 Jul;96(1):95-8. PMID: 7607663 Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. PMID: 23913538 Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612. PMID: 17311297 Zhu L et al. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. Medicine (Baltimore). 2016 Mar;95(10):e3043. PMID: 26962827 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 03, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2021 | - - |
Neurofibromatosis, type 1;C0553580:Ewing sarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Oncology Initiative, University of California, San Francisco | Sep 04, 2018 | - - |
NF1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 27, 2023 | The NF1 c.6855C>A variant is predicted to result in premature protein termination (p.Tyr2285*). This variant has also been referred to as c.6792C>A (p.Tyr2264*) in an alternate transcript (NM_000267.3). This variant has been identified in several unrelated individuals with neurofibromatosis type I and was found to be de novo in multiple cases (see for example, Robinson et al. 1995. PubMed ID: 7607663; Wimmer et al. 2007. PubMed ID: 17311297; Sabbagh et al. 2013. PubMed ID: 23913538; Zhu et al. 2016. PubMed ID: 26962827). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185082/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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 | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Juvenile myelomonocytic leukemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 18, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 2015 | The p.Y2285*pathogenic mutation (also known as c.6855C>A) located in coding exon 46 of the NF1 gene, results from a C to A substitution at nucleotide position 6855. This changes the amino acid from a to a stop codon within coding exon 46.This is a recurrent mutation that has been detected in multiple patients and families with NF1 and has also been reported to result in-frame skipping of exon 37 (Robinson PN et al. Hum. Genet. 1995 Jul;96(1):95-8,Wimmer K et al. Hum. Mutat. 2007 Jun; 28(6):599-612,Sabbagh A et al. Hum. Mutat. 2013 Nov; 34(11):1510-8). In addition to the clinical information 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). This mutation is also known asp.Y2264* (c.6792C>A) in published literature. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;D
Vest4
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at