rs201742496
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_014845.6(FIG4):c.1405G>A(p.Gly469Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000919 in 1,609,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014845.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251404Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135876
GnomAD4 exome AF: 0.0000960 AC: 140AN: 1457726Hom.: 0 Cov.: 27 AF XY: 0.0000813 AC XY: 59AN XY: 725490
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:2
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FIG4: PM2 -
Inborn genetic diseases Uncertain:1
Nicholson, 2011; DiVincenzo, 2014 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
FIG4-related disorder Uncertain:1
The FIG4 c.1405G>A variant is predicted to result in the amino acid substitution p.Gly469Arg. This variant has been reported in individuals with Charcot-Marie-Tooth disease, although pathogenicity has not been established (Nicholson et al. 2011. PubMed ID: 21705420; DiVincenzo et al. 2014. PubMed ID: 25614874). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-110085156-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Charcot-Marie-Tooth disease type 4 Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 469 of the FIG4 protein (p.Gly469Arg). This variant is present in population databases (rs201742496, gnomAD 0.006%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21705420). ClinVar contains an entry for this variant (Variation ID: 585869). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at