GATA2 c.619dup, p.Asp207GlyfsTer75
NM_001145661.1:c.619dup
Pathogenic
This frameshift variant (D207Gfs*75) in GATA2 leads to loss of function, is absent from controls, and has strong functional evidence of damaging effect. Combined PVS1, PS3, and PM2 support a classification of Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
GATA2
Transcript
NM_001145661.2
Total Exons
7
Strand
Reverse (−)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001145661.1 | Alternative | 7 exons | Reverse |
Variant Details
HGVS Notation
NM_001145661.1:c.619dup
Protein Change
D207Gfs*75
Location
Exon 4
(Exon 4 of 7)
5'Exon Structure (7 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 207 in gene GATA2
Variant interpretation based on transcript NM_001145661.2
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HGVS InputNM_001145661:c.619dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 207 in gene GATA2
Functional Summary
The GATA2 D207Gfs*75 variant is a truncating mutation that results in the loss of protein expression. Functional evidence indicates that truncating mutations in GATA2, particularly in the ZF1 and ZF2 domains, are associated with hematological malignancies and poor prognosis. In vivo studies demonstrate that loss of GATA2 function leads to increased leukemogenesis, supporting a damaging effect of this variant.
Database Previews
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, start codon, splicing ±1 or 2, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: NM_001145661.1:c.619dupG (D207Gfs*75) is a frameshift leading to premature truncation in GATA2, a gene with a known loss-of-function disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a LOF gene.
PS1
PS1 (Not Applied) Strength Modified
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: there is no known pathogenic variant producing the same D207 amino acid change. Therefore, this criterion is not applied because no matching known pathogenic amino acid change exists.
PS2
PS2 (Not Applied) Strength Modified
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 de novo data are provided. Therefore, this criterion is not applied because de novo status is not confirmed.
PS3
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 D207Gfs*75 results in loss of protein expression and increased leukemogenesis. Therefore, this criterion is applied at Strong strength because functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
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 or prevalence data are provided. Therefore, this criterion is not applied because case-control data are lacking.
PM1
PM1 (Not Applied) Strength Modified
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: codon 207 is outside the GATA2 zinc-finger domains (ZF1 and ZF2) and no hotspot is described. Therefore, this criterion is not applied because it is not in a known hotspot or critical domain.
PM2
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 absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because it is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
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: GATA2 disorders are autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied because PM3 is not applicable for a dominant gene.
PM4
PM4 (Not Applied) Strength Modified
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 is a frameshift leading to truncation, not an in-frame change or stop-loss. Therefore, this criterion is not applied because the variant is not an in-frame indel or stop-loss.
PM5
PM5 (Not Applied) Strength Modified
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: it is a frameshift, not a missense change. Therefore, this criterion is not applied because PM5 pertains only to missense variants.
PM6
PM6 (Not Applied) Strength Modified
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 or de novo information is provided. Therefore, this criterion is not applied because de novo status is not documented.
PP1
PP1 (Not Applied) Strength Modified
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 or family data are provided. Therefore, this criterion is not applied because segregation data are lacking.
PP2
PP2 (Not Applied) Strength Modified
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: it is a frameshift, not a missense. Therefore, this criterion is not applied because PP2 applies only to missense variants.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: SpliceAI predicts minimal splicing impact (max score 0.03) and the variant effect is truncating. Computational evidence does not add further support. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
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 or family history data are provided. Therefore, this criterion is not applied because phenotype specificity is not documented.
PP5
PP5 (Not Applied) Strength Modified
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: it is not found in ClinVar or other curated sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
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: MAF is 0%, well below BA1 thresholds. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
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: MAF is 0%, below expected maximum. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
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 data on healthy carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
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 effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
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 are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease". The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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: it is not an in-frame indel nor in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: truncating effect overrides computational splicing predictions. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
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 is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
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: it is not reported as benign in any source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
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 a frameshift, not synonymous. Therefore, this criterion is not applied.