rs1064797084
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_002017.5(FLI1):c.1028A>G(p.Tyr343Cys) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002017.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLI1 | NM_002017.5 | c.1028A>G | p.Tyr343Cys | missense_variant | Exon 9 of 9 | ENST00000527786.7 | NP_002008.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Bleeding disorder, platelet-type, 21 Pathogenic:2
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not provided Pathogenic:1Uncertain:1
Published functional studies suggest a damaging effect with luciferase assays revealing that the transcriptional activity of Y343C was significantly reduced compared to wildtype (PMID: 24100448); 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; Identified heterozygous in two relatives from a single family with confirmed platelet dense granule secretion defect, mild thrombocytopenia, excessive bleeding, and absent thrombin-induced ATP secretion in platelets (PMID: 27479822, 24100448); This variant is associated with the following publications: (PMID: 27479822, 35021601, 37377909, 24100448) -
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. Experimental studies have shown that this missense change affects FLI1 function (PMID: 24100448). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 424633). This missense change has been observed in individual(s) with clinical features of FLI1-related conditions (PMID: 24100448). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 343 of the FLI1 protein (p.Tyr343Cys). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at