5-171870796-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_001378974.1(FBXW11):c.1403G>A(p.Arg468Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001378974.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBXW11 | NM_001378974.1 | c.1403G>A | p.Arg468Gln | missense_variant | Exon 11 of 14 | ENST00000517395.6 | NP_001365903.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461700Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727168
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurodevelopmental, jaw, eye, and digital syndrome Pathogenic:2
This variant is interpreted as likely pathogenic for Neurodevelopmental, jaw, eye, and digital syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2 downgraded to moderate); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2). -
PS2, PM1, PM2, PM5, PP2, PP3 -
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; A different likely pathogenic missense change at this residue (p.R447L) has been reported in the published literature in association with FBXW11-related neurodevelopmental disorder; This variant is associated with the following publications: (PMID: 31402090) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at