5-180603391-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_182925.5(FLT4):c.3894-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,613,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_182925.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLT4 | ENST00000261937.11 | c.3894-1G>A | splice_acceptor_variant, intron_variant | Intron 29 of 29 | 1 | NM_182925.5 | ENSP00000261937.6 | |||
FLT4 | ENST00000502603.5 | n.594-1G>A | splice_acceptor_variant, intron_variant | Intron 3 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247074Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133894
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461330Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726922
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: FLT4 c.3894-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 3-prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 247074 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3894-1G>A in individuals affected with FLT4-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at