About GATA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GATA2 c.953C>T, p.(Ala318Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under non-VCEP generic ACMG thresholds, absence from large population databases meets PM2 at supporting strength (allele frequency < 0.1%).
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect: REVEL score 0.952 (strongly deleterious, above 0.5 threshold) and BayesDel score 0.604845 (above deleterious threshold). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a purely missense effect. The convergence of multiple computational algorithms supports a deleterious impact on protein function.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GATA2, a transcription factor, is recurrently mutated in hematological malignancies and various solid tumors.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
29 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62003236, n = 29 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 7 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001145661.1:c.953C>T (p.Ala318Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
Multiple in silico predictors support a deleterious effect on protein function, with REVEL score 0.952 and BayesDel score 0.604845, meeting PP3 at supporting strength.
This variant is classified as Uncertain Significance in ClinVar (1 clinical laboratory, criteria provided, single submitter). No expert panel classification is available.
PMID:22649106 reports functional characterization of a different substitution at the same residue (A318T) showing reduced CEBPA-mediated transcriptional activation in a somatic AML context, but the exact variant p.Ala318Val was not tested and cannot be used to meet PS3 or BS3.
No CSPEC/VCEP framework exists for GATA2. Assessment follows generic ACMG/AMP 2015 rules (PMID:25741868) with final classification combining rules from the same source.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under non-VCEP generic ACMG thresholds, absence from large population databases meets PM2 at supporting strength (allele frequency < 0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- gnomAD v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes).
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.952 (strongly deleterious, above 0.5 threshold) and BayesDel score 0.604845 (above deleterious threshold). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a purely missense effect. The convergence of multiple computational algorithms supports a deleterious impact on protein function. Details ▾Hide ▴
Evidence considered
- REVEL score 0.952 (deleterious). BayesDel score 0.604845 (deleterious). SpliceAI max delta 0.00 (no cryptic splice effect
- consistent with computational assessment focused on missense impact).
Sources
Not met · 7 · evaluated, threshold not reached
PM1 The variant lies within the ZF1 domain of GATA2, which is a critical functional domain for DNA binding and transcriptional regulation. However, cancer hotspot analysis for this exact variant was negative, and no GATA2-specific VCEP/ClinGen PM1 domain specification exists. Without a domain-level PM1 framework for GATA2, this criterion cannot be met under generic ACMG rules. Details ▾Hide ▴
Evidence considered
- Residue A318 lies in ZF1 domain
- PMID:22649106 confirms recurrent somatic mutations at this residue in AML. Cancer hotspot analysis negative for this exact variant.
Still missing
- No GATA2-specific VCEP PM1 domain specification. Hotspot analysis for this exact variant is negative.
Sources
PP5 This variant is classified as Uncertain Significance (not Pathogenic or Likely Pathogenic) by the sole ClinVar submitter (Labcorp Genetics, SCV004589994, criteria provided, single submitter). No expert panel has classified this variant as pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (1 submitter
- criteria provided
- single submitter). No expert panel classification.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 1% in any population database. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD databases
- allele frequency is 0.00
- well below the 1% BA1 threshold.
Sources
BS1 This variant is absent from all gnomAD databases. BS1 requires an allele frequency > 0.3% in population databases. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD databases
- allele frequency is 0.00
- well below the 0.3% BS1 threshold.
Sources
BS3 The only functional study identified (PMID:22649106) tested a different substitution at the same residue (A318T, not A318V) and showed reduced — not normal — transcriptional activation, which is consistent with a damaging effect. No functional evidence demonstrates no deleterious impact for p.Ala318Val. Details ▾Hide ▴
Evidence considered
- PMID:22649106 functional data for A318T at same residue shows reduced CEBPA-mediated transcriptional activation (damaging
- not benign). A318V was not tested.
Sources
BP4 Multiple in silico predictors support a deleterious effect: REVEL score 0.952 and BayesDel score 0.604845 both exceed thresholds for predicted pathogenicity. BP4 requires computational evidence supporting no impact on gene product. Details ▾Hide ▴
Evidence considered
- REVEL 0.952 (deleterious) and BayesDel 0.604845 (deleterious) contradict BP4
- supporting a damaging effect instead.
Sources
revelbayesdel
BP6 This variant is classified as Uncertain Significance (not Benign or Likely Benign) by the sole ClinVar submitter. BP6 requires a reputable source to have reported the variant as benign. Details ▾Hide ▴
Not assessed · 7 · no assessment recorded
PS1 Requires a different amino acid change at the same residue previously established as pathogenic. No pathogenic A318 variant was identified in ClinVar or the literature reviewed. Details ▾Hide ▴
Still missing
- No pathogenic comparator variant identified at residue A318 in any database or publication reviewed.
PS3 Functional data exist for a different substitution at the same residue (A318T in PMID:22649106, showing reduced CEBPA-mediated transcriptional activation in HEK293T reporter assays), but the exact variant p.Ala318Val was not tested. Cannot assign PS3 without variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- PMID:22649106 reports functional data for A318T (not A318V) at the same residue in somatic AML context.
Still missing
- No variant-specific functional assay for p.Ala318Val. Functional data for A318T at the same residue are suggestive but do not meet PS3 threshold for the exact variant.
PS4 No case-control or prevalence data comparing variant frequency in affected vs. unaffected cohorts are available. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data available.
PP1 No segregation data are available for this variant. No family studies with co-segregation of this variant and disease phenotype were identified. Details ▾Hide ▴
Still missing
- No segregation or family co-segregation data available.
PP2 HCI prior gene-level constraint score is not available for GATA2. PP2 requires evidence that missense variants are a common mechanism of disease in a gene with a low rate of benign missense variation, which cannot be assessed without gene-specific constraint metrics. Details ▾Hide ▴
Evidence considered
- HCI prior not available for GATA2.
Still missing
- No gene-level missense constraint metric (HCI prior) available for GATA2.
PP4 No patient phenotype or clinical information is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for the gene, which cannot be evaluated without clinical data. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical data available for assessment.
BS2 No data on observation of this variant in healthy adult individuals in the absence of disease. BS2 requires the variant to be observed in a healthy adult with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy adult observation data available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001145661.1:c.953C>T is a missense variant (p.Ala318Val). It does not fall into any default PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework under PMC6185798 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant outside PVS1 null-variant buckets
- ClinGen SVI PVS1 decision tree does not assign default strength for this variant class.
Sources
PS2 N/ANo de novo data are available for this variant. No parentage-confirmed de novo observation was identified in ClinVar, the literature reviewed, or any other evidence source. Details ▾Hide ▴
Still missing
- No de novo or trio data available.
PM5 N/ANo established pathogenic missense variant at the same amino acid residue (A318) was identified in ClinVar. Automated PM5 candidate harvesting found no clinically classified comparator variants. PMID:22649106 reports A318T in a somatic AML context without a pathogenic germline classification. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator at residue A318 identified in ClinVar or literature.
Sources
pm5_candidates
PM6 N/ANo de novo observation is available for this variant. No parentage data or de novo reports were identified in ClinVar or the literature reviewed. Details ▾Hide ▴
Still missing
- No de novo data available.
BS4 N/ANo segregation data are available to assess lack of segregation with disease. No family studies involving this variant were identified. Details ▾Hide ▴
Still missing
- No segregation or family data available.
BP1 N/AGATA2 disease is caused by both truncating and missense variants (including missense variants in ZF1 and ZF2 domains). BP1 is restricted to genes where primarily truncating variants cause disease, which does not apply to GATA2. Details ▾Hide ▴
Evidence considered
- GATA2 deficiency syndrome is caused by both loss-of-function and missense variants
- BP1 does not apply.
Sources
pvs1_gene_context
BP2 N/ANo phase data are available to assess observation in trans with a pathogenic variant. No cis/trans phase information was identified for this variant. Details ▾Hide ▴
Still missing
- No phase data available.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. NM_001145661.1:c.953C>T is a missense substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo data are available indicating this variant was found in a case with an alternate molecular basis for disease. No such co-occurrence evidence was identified in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001145661.1:c.953C>T is a missense variant (p.Ala318Val), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 sequence variant interpretation framework (PMID:25741868). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- GATA2
- Transcript
- NM_001145661.1
- Coding (HGVS c.)
- NM_001145661.1:c.953C>T
- Protein (HGVS p.)
- NP_001139133.1:p.(Ala318Val)
- GRCh38
- chr3:128483924 G>A
- GRCh37
- chr3:128202767 G>A
- ClinVar
- 2941214
- COSMIC
- COSV62003236
Gene diagram
Every interpreted variant in GATA2, mapped onto the exon structure of NM_001145661.1. Select a row to find it on the plot.
GATA2NM_001145661.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GATA2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.952
- BayesDel
- 0.605
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.952 (strongly deleterious, above 0.5 threshold) and BayesDel score 0.604845 (above deleterious threshold). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a purely missense effect. The convergence of multiple computational algorithms supports a deleterious impact on protein function. Details ▾Hide ▴
Evidence considered
- REVEL score 0.952 (deleterious). BayesDel score 0.604845 (deleterious). SpliceAI max delta 0.00 (no cryptic splice effect
- consistent with computational assessment focused on missense impact).
Sources
BP4 Multiple in silico predictors support a deleterious effect: REVEL score 0.952 and BayesDel score 0.604845 both exceed thresholds for predicted pathogenicity. BP4 requires computational evidence supporting no impact on gene product. Details ▾Hide ▴
Evidence considered
- REVEL 0.952 (deleterious) and BayesDel 0.604845 (deleterious) contradict BP4
- supporting a damaging effect instead.
Sources
revelbayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001145661.1:c.953C>T is a missense variant (p.Ala318Val), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.952. BayesDel score = 0.604845.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 22649106 ↗GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.Reports recurrent GATA2 ZF1 mutations in biallelic CEBPA-mutated AML. Functional assays in HEK293T cells show that A318T (a different substitution at the same residue) reduces CEBPA-mediated transcriptional activation. NM_001145661.1:c.953C>T (p.Ala318Val) was not identified in this paper.Does not name this variant
Quoted passage
the GATA2 mutants Ala318Thr and Leu321Phe showed reduced activation
Results: Table 1 (patient 1 carries L321V, not A318V); Methods (Plasmids section lists tested mutants: A318T, G320D, L321V, R293Q, V296G, L359V); Figure 3 (A318T functional data)
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2941214/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-128202767-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-128483924-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-128483924-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001145661.1%3Ac.9…
- OncoKB ↗www.oncokb.org/gene/GATA2/A318V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=130223663
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2941214)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.952. BayesDel score = 0.604845.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GATA2, a transcription factor, is recurrently mutated in hematological malignancies and various solid tumors.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62003236, n = 29 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.