NM_182925.5:c.2563G>A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_182925.5(FLT4):c.2563G>A(p.Ala855Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,342 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_182925.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000919 AC: 14AN: 152268Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000820 AC: 2AN: 243830Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132808
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1459956Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726282
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152386Hom.: 0 Cov.: 34 AF XY: 0.0000805 AC XY: 6AN XY: 74522
ClinVar
Submissions by phenotype
Hereditary lymphedema type I Pathogenic:1
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not specified Uncertain:1
Variant summary: FLT4 c.2563G>A (p.Ala855Thr) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 243830 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2563G>A has been reported in the literature in a homozygous proband affected with lymphoedema from a consanguineous family. However, parents who were heterozygous for this variant had no clinical signs of lymphoedema indicating variant did not segregate with disease in this family (example: Ghalamkarpour_2009). This report does not provide unequivocal conclusions about association of the variant with FLT4-Related Disorders. One publication reports experimental evidence that phosphorylation of the A855T mutant FLT4/VEGFR3 is weak upon VEGF-C induction. However, this report does not allow convincing conclusions about the variant effect (example: Ghalamkarpour_2009). The following publication has been ascertained in the context of this evaluation (PMID: 19289394). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Observed in the homozygous state in a patient in published literature with congenital lymphedema whose heterozygous parents were unaffected, and not observed in the homozygous state in controls (Ghalamkarpour et al., 2009); Published functional studies suggest a damaging effect: impaired ligand induced internalization, impaired ERK1/2 activity, and reduced receptor phosphorylation (Ghalamkarpour et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10835628, 11114740, 23074044, 19289394) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at