17-31230373-T-G
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.3104T>G(p.Met1035Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461118Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726856
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
The NF1 c.3104T>G (p.Met1035Arg) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with neurofibromatosis type 1 and LEOPARD syndrome, suggesting that the phenotype associated with this variant may be broader than traditional NF1 (PMID: 8807336; 31766501). ?In summary, this variant meets criteria to be classified as likely pathogenic.? -
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This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1035 of the NF1 protein (p.Met1035Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type I (NF1), Neurofibromatosis-Noonan syndrome (NFNS), and/or Noonan syndrome with multiple lentigines (LEOPARD syndrome) (PMID: 8807336; Invitae). ClinVar contains an entry for this variant (Variation ID: 347). 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 expected to disrupt NF1 protein function. This variant disrupts the p.Met1035 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042399, 24789688; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16542390, 24803665, 24789688, 9042399, 31487937, 30843352, 25486365, 2121369, 31766501, 8807336) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at