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 E598delinsATLISENMK variant has been functionally characterized as likely oncogenic. It is located in a statistically significant hotspot within the juxtamembrane domain of the FLT3 protein. Functional studies of similar juxtamembrane domain mutations in FLT3 have demonstrated activating effects, including increased growth factor-independent proliferation and induction of a myeloproliferative phenotype in various cell lines and in vivo models.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.07 | -140 bp |
| Donor Loss (DL) | 0.01 | 175 bp |
| Acceptor Gain (AG) | 0.08 | 8 bp |
| Donor Gain (DG) | 0.01 | 81 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: the variant is an in-frame insertion/deletion and does not create a null allele. Therefore, this criterion is not applied because the variant is not a predicted loss-of-function.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "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 reported as pathogenic via a different nucleotide alteration. Therefore, this criterion is not applied because there is no prior known pathogenic variant at the same residue.
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 occurrence or parental testing. Therefore, this criterion is not applied due to lack of inheritance data.
PS3 (Strong)
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: in vitro and in vivo studies demonstrate that the FLT3 E598delinsATLISENMK variant is activating, leading to growth factor–independent proliferation and a myeloproliferative phenotype. Therefore, this criterion is applied at Strong strength because well-established functional assays support a damaging gain-of-function effect.
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 frequency data comparing affected versus controls. Therefore, this criterion is not applied due to absence of prevalence data.
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: the insertion is within the statistically significant juxtamembrane domain hotspot of FLT3, a region critical for autoinhibition and known to harbor activating mutations. Therefore, this criterion is applied at Moderate strength because the variant lies in a recognized mutational hotspot.
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: it is not present in gnomAD, ExAC, 1000 Genomes, or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large control populations.
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 with another variant. Therefore, this criterion is not applied because the variant is not evaluated in a recessive context with a second allele.
PM4 (Moderate)
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: it causes deletion of E598 and insertion of eight amino acids, altering protein length. Therefore, this criterion is applied at Moderate strength because the in-frame indel changes protein length in a non-repeat region.
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: there is no reported pathogenic missense change at the same residue for comparison. 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 information on de novo assumption. Therefore, this criterion is not applied due to lack of inheritance data.
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 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 insertion/deletion, not a simple missense. 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/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: computational tools including SpliceAI predict no significant impact. Therefore, this criterion is not applied because in silico evidence does not support pathogenicity.
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 specific 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 databases. 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 (based on population data)". The evidence for this variant shows: allele frequency is zero, not above threshold. 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: allele frequency is zero, not greater than expected. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance 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 damaging gain-of-function. 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: disease mechanism is gain-of-function, not isolated to loss-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 such observations. 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: 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". The evidence for this variant shows: SpliceAI predicts minimal splicing impact and other in silico tools do not indicate deleterious effect. Therefore, this criterion is applied at Supporting strength because computational data suggest no functional 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 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 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: it is not a synonymous change. Therefore, this criterion is not applied.