6-109743137-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_014845.6(FIG4):c.904G>A(p.Glu302Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,846 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014845.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250784Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135520
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460714Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726674
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4J Pathogenic:2
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Bilateral parasagittal parieto-occipital polymicrogyria Uncertain:1
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Charcot-Marie-Tooth disease type 4 Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 302 of the FIG4 protein (p.Glu302Lys). This variant is present in population databases (rs587777714, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Charcot-Marie-Tooth disease (PMID: 21705420). ClinVar contains an entry for this variant (Variation ID: 156015). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FIG4 function (PMID: 21705420). 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