NM_001042492.3:c.1431T>A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001042492.3(NF1):c.1431T>A(p.Phe477Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F477F) has been classified as Likely benign.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
Publications
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1431T>A | p.Phe477Leu | missense_variant | Exon 13 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.4 | c.1431T>A | p.Phe477Leu | missense_variant | Exon 13 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1431T>A | p.Phe477Leu | missense_variant | Exon 13 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NF1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 477 of the NF1 protein (p.Phe477Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The p.F477L variant (also known as c.1431T>A), located in coding exon 13 of the NF1 gene, results from a T to A substitution at nucleotide position 1431. The phenylalanine at codon 477 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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