Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004119.3 | MANE Select | 3826 nt | 67–3048 |
| NM_004119.2 | RefSeq Select | 3848 nt | 83–3064 |
| NM_004119.1 | Alternative | 3475 nt | 58–3039 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.09 | 127 bp |
| Donor Loss (DL) | 1.0 | 3 bp |
| Acceptor Gain (AG) | 0.15 | 0 bp |
| Donor Gain (DG) | 0.99 | 0 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: a complex duplication spanning coding and intronic sequence in FLT3 which is a known gain-of-function gene, not a LoF gene. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no known amino acid change has been established and the protein change is not defined. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no information on de novo status or parental testing. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied.
PM1 (Moderate)
According to standard ACMG guidelines the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: FLT3 internal tandem duplications in the juxtamembrane domain (exons 14/15) are a well-established mutational hotspot driving gain of function in AML. Therefore, this criterion is applied at Moderate strength.
PM2 (Moderate)
According to standard ACMG guidelines the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: not found in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength.
PM3 (Not Applied)
According to standard ACMG guidelines the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". The evidence for this variant shows: no data on trans configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: complex duplication including intronic sequence with uncertain impact on protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no missense change or known pathogenic residue alteration. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no parental testing data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: not a simple missense substitution. Therefore, this criterion is not applied.
PP3 (Supporting)
According to standard ACMG guidelines the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: SpliceAI predicts a maximal score of 1.0 for donor loss, indicating high likelihood of splice disruption. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to standard ACMG guidelines the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: allele frequency is zero. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: not observed in population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines the rule for BS2 is: "Observed in healthy adult individuals with full penetrance expected at an early age". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: not a simple missense and FLT3 disease mechanism is gain-of-function. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: not a simple in-frame event in a known repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: computational evidence indicates splice disruption. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: not reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: not a synonymous change. Therefore, this criterion is not applied.