rs201047812
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP2BP4_ModerateBP6BS2_Supporting
The NM_001042492.3(NF1):c.3436G>A(p.Val1146Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1146D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3436G>A | p.Val1146Ile | missense_variant | 26/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3436G>A | p.Val1146Ile | missense_variant | 26/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3436G>A | p.Val1146Ile | missense_variant | 26/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000132 AC: 20AN: 152068Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000127 AC: 32AN: 251366Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135860
GnomAD4 exome AF: 0.000207 AC: 303AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.000184 AC XY: 134AN XY: 727236
GnomAD4 genome ? AF: 0.000132 AC: 20AN: 152068Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11AN XY: 74264
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:5Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Aug 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 24, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 24, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2016 | The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also been identified in 11/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201047812). An additional amino a cid change at this position (p.Val1164 Phe) has been reported to occur de novo i n two individuals with NF1 (Mendelian Genes), suggesting that a change at this p osition may not be tolerated. However, valine (Val) at position 1146 is not cons erved in evolutionary distant species, with multiple fish species carrying an is oleucine (Ile) at this position, and raising the possibility that a change at th is position may be tolerated. Additional computational prediction tools suggest that the p.Val1146Ile variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, due to conflic ting data, the clinical significance of the p.Val1146Ile variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2019 | Variant summary: NF1 c.3436G>A (p.Val1146Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251366 control chromosomes, predominantly observed within the Latino subpopulation (at a frequency of 0.00023) and the in the European (Non-Finnish) subpopulation (at frequency of 0.00019) in the gnomAD database. The variant frequency in the Latino subpopulation is higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00023 vs 0.00021), suggesting that the variant is might be benign. In addition, the variant occurs in certain European subpopulations with even higher frequencies (e.g. in the Bulgarians (0.0015), and in Southern Europeans (0.00026)) further supporting a benign role. The c.3436G>A variant has been reported in the literature in an individual affected with Neurofibromatosis Type 1, however these publications cited the variant as a polymorphism (Trovo_2004, Trovo-Marqui_2005). Therefore these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. A co-occurrence with another pathogenic NF1 variant has been reported (NF1 c.3892C>T (p.Gln1298X) in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified the variant as VUS, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 06, 2021 | The NF1 c.3436G>A; p.Val1146Ile variant (rs201047812) is reported in the literature in individuals affected with neurofibromatosis type 1 or another unspecified cancer, but without clear association with disease (Trovo-Marqui 2005, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 141451), and is found in the general population with an overall allele frequency of 0.012% (33/282760 alleles) in the Genome Aggregation Database. The valine at codon 1146 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Due to limited information, the clinical significance of the p.Val1146Ile variant is uncertain at this time. References: Trovo-Marqui AB et al. High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Braz J Med Biol Res. 2005 Sep;38(9):1441-7. PMID: 16138229. Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 03, 2023 | The frequency of this variant in the general population, 0.00023 (8/35432 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in patients with Neurofibromatosis, type 1 (PMIDs: 23656349 (2014) and 16138229 (2005)) and breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The variant has been reported as a somatic finding in a glioma tumor sample (PMID: 31891871 (2020)). In addition, this variant has been reported in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2020 | This variant is associated with the following publications: (PMID: 31159747, 15627836, 16138229, 23656349, 31891871) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 23, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2015 | Does not segregate with disease in family study (genes with incomplete penetrance);in silico models in agreement (benign);Other data supporting benign classification - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Neurofibromatosis, familial spinal Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Neurofibromatosis-Noonan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Café-au-lait macules with pulmonary stenosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at