rs1555615480
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_001042492.3(NF1):c.3830G>A(p.Gly1277Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. G1277A) 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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3830G>A | p.Gly1277Asp | missense_variant | 28/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3830G>A | p.Gly1277Asp | missense_variant | 28/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3830G>A | p.Gly1277Asp | missense_variant | 28/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 2179936). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1277 of the NF1 protein (p.Gly1277Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at