17-31095355-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_001042492.3(NF1):c.46C>T(p.Arg16Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.46C>T | p.Arg16Cys | missense_variant | Exon 1 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.46C>T | p.Arg16Cys | missense_variant | Exon 1 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.46C>T | p.Arg16Cys | missense_variant | Exon 1 of 15 | NP_001121619.1 | ||
MIR4733HG | NR_186435.1 | n.136G>A | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1387796Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 684830
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
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This variant has not been reported in the literature in individuals affected with NF1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 378270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 16 of the NF1 protein (p.Arg16Cys). -
not provided Uncertain:1
The R16C variant in the NF1 gene has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The R16C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analyses predict that this variant is probably damaging to the protein structure and function. A missense variant in the same residue (R16P) has been reported in an individual with clinical featues and a family history associated with neurofibromatosis (Nemethova et al., 2013), supporting the functional importance of this region of the protein. We interpret R16C as a variant of uncertain significance -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The p.R16C variant (also known as c.46C>T), located in coding exon 1 of the NF1 gene, results from a C to T substitution at nucleotide position 46. The arginine at codon 16 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at