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
The FLT3 E598_Y599insTIDFREYE variant has been functionally characterized as activating. It is located in the juxtamembrane domain of the FLT3 protein and has been shown to increase growth factor-independent proliferation and induce a myeloproliferative phenotype in various cell lines and an in vivo bone marrow transplant model, indicating a damaging effect.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.06 | 131 bp |
| Donor Loss (DL) | 0.02 | 165 bp |
| Acceptor Gain (AG) | 0.04 | 10 bp |
| Donor Gain (DG) | 0.0 | -37 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is an in‐frame insertion, not predicted to result in loss of function. 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 variant produces the identical E598_Y599insTIDFREYE amino acid change. 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 parental testing or segregation data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: functional studies demonstrate that E598_Y599insTIDFREYE increases growth factor-independent proliferation and induces a myeloproliferative phenotype. Therefore, this criterion is applied at Strong strength because well-established assays show a damaging activating effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls.' The evidence for this variant shows: no case–control or large cohort 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 and/or critical and well-established functional domain without benign variation.' The evidence for this variant shows: the insertion lies within the juxtamembrane domain of FLT3, a known hotspot for activating insertions. Therefore, this criterion is applied at Moderate strength because the variant precisely falls in a functional hot spot.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in population databases.' The evidence for this variant shows: it is not found in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
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 in a recessive context. Therefore, this criterion is not applied.
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: it is an in-frame insertion of eight amino acids in a non-repetitive region. Therefore, this criterion is applied at Moderate strength because the insertion alters protein length.
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 before.' The evidence for this variant shows: it is not a missense change and no pathogenic missense variants at these positions have been reported. 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 information is available. 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 family 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 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.' The evidence for this variant shows: it is an in-frame insertion, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
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.' The evidence for this variant shows: in silico tools including SpliceAI predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports the variant as pathogenic, but the evidence is not available to the laboratory.' The evidence for this variant shows: not present in ClinVar or other reputable variant databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is greater than expected for 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 disorder.' The evidence for this variant shows: allele frequency is zero. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a recessive (homozygous) or dominant (heterozygous) disorder when full penetrance is expected at an early age.' The evidence for this variant shows: no observations in healthy individuals. 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: functional studies demonstrate a damaging activating effect. 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 for which only loss of function causes disease.' The evidence for this variant shows: it is an in-frame insertion, not missense. 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 a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: no data on cis/trans configuration. 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 a known function.' The evidence for this variant shows: the insertion is not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
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: in silico predictions including SpliceAI show minimal impact on splicing and no predicted deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates likely benign impact.
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 alternate molecular basis reported. 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 the evidence is not available.' The evidence for this variant shows: no such report. 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: it is not a synonymous change. Therefore, this criterion is not applied.