17-31206243-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting
The NM_001042492.3(NF1):c.1264G>T(p.Ala422Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1264G>T | p.Ala422Ser | missense_variant | Exon 12 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.1264G>T | p.Ala422Ser | missense_variant | Exon 12 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1264G>T | p.Ala422Ser | missense_variant | Exon 12 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251378Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461268Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726972
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 422 of the NF1 protein (p.Ala422Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1398490). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. -
Juvenile myelomonocytic leukemia Uncertain:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The p.A422S variant (also known as c.1264G>T), located in coding exon 12 of the NF1 gene, results from a G to T substitution at nucleotide position 1264. The alanine at codon 422 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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