rs199474760
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.1748A>G(p.Lys583Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K583E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1748A>G | p.Lys583Arg | missense_variant | 16/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.1748A>G | p.Lys583Arg | missense_variant | 16/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1748A>G | p.Lys583Arg | missense_variant | 16/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460616Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726674
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | May 24, 2023 | PS4, PM1, PM2, PM5, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 02, 2022 | - - |
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 | Invitae | Jan 26, 2024 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 583 of the NF1 protein (p.Lys583Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16944272, 17726231, 18041031, 21354044, 27074763, 27322474, 31370276). ClinVar contains an entry for this variant (Variation ID: 68306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 16 (PMID: 18041031, 27322474; Invitae). This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu578Pro) have been determined to be pathogenic (PMID: 12746402, 16479075, 17426081, 23668869, 25211147). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jan 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2023 | RNA studies indicate this variant leads to the creation of a cryptic splice site and the loss of 27 base pairs (Brinckmann et al., 2007; Valero et al., 2011, Evans et al., 2016) within the critical GTPase activating protein domain (Luo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22155606, 16944272, 24803665, 17726231, 28068329, 10712197, 18041031, 27322474, 27074763, 25541118, 21354044, 30308447, 31370276, 34418705, 34308104, 25486365) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at