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 M578_Y599dup variant has been functionally characterized as an activating mutation. It is located in the juxtamembrane domain of the FLT3 protein and has been shown to induce increased growth factor-independent proliferation and a myeloproliferative phenotype in various cell lines and an in vivo model. This evidence supports a damaging effect, consistent with its role in acute myeloid leukemia.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.03 | 85 bp |
| Donor Loss (DL) | 0.03 | 168 bp |
| Acceptor Gain (AG) | 0.18 | 13 bp |
| Donor Gain (DG) | 0.02 | 0 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease'. The evidence for this variant shows: NM_004119.2:c.1732_1797dup is an in-frame duplication, not a null LoF variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: No identical amino acid change has been previously reported as pathogenic. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – 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 or de novo data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: The FLT3 M578_Y599dup variant has been functionally characterized as an activating mutation in cell lines and an in vivo model, inducing growth factor–independent proliferation and a myeloproliferative phenotype. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate a damaging gain-of-function effect consistent with disease mechanism.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: No case–control or prevalence data are available. Therefore, this criterion is not applied.
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: It is located in the juxtamembrane domain of FLT3, a well-established hotspot for internal tandem duplication mutations that activate kinase function in acute myeloid leukemia. Therefore, this criterion is applied at Moderate strength because the variant lies within a known functional hotspot critical for regulation.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: It is absent from population databases including gnomAD (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not observed in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: No trans‐configuration data with another pathogenic variant are available; FLT3 internal tandem duplications act dominantly. Therefore, this criterion is not applied.
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: NM_004119.2:c.1732_1797dup results in an in-frame duplication of amino acids M578_Y599, altering protein length. Therefore, this criterion is applied at Moderate strength because the duplication changes protein length.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: This is an in-frame duplication, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: No de novo assumption data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: No family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – 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: This is an in-frame duplication, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: SpliceAI predicts minimal impact on splicing (max delta score 0.18) and no other in silico tool predicts deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: No phenotype or clinical data were provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: No such reports are available. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder'. The evidence for this variant shows: Allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: Allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: No observations in healthy individuals are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – 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: 'BS4 – Lack of segregation in affected family members'. The evidence for this variant shows: No family segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: This is an in-frame duplication in an oncogene where gain-of-function is pathogenic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant when that configuration is known to be benign'. The evidence for this variant shows: No such configuration data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: The duplication occurs in a functional juxtamembrane domain, not a benign repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: SpliceAI predicts no significant splicing impact (max delta score 0.18) and other in silico tools do not predict deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect on splicing, though it is outweighed by functional and other pathogenic evidence.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: No such case data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: No such report is available. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: NM_004119.2:c.1732_1797dup is not synonymous. Therefore, this criterion is not applied.