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.1 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.2 This variant is classified as Uncertain Significance in ClinVar (1 clinical laboratory, criteria provided, single submitter). No expert panel classification is available.3 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 BS3.4 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.5
GATA2
Final classification
VUS
GATA2 c.953C>T · p.Ala318Val
GATA2
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.
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.
Classification rationale
PM2PP3
VUS
GATA2 c.953C>T
PM2 + PP3
→
VUS
2
revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_001145661.1 · variants mapped to exon structure
GATA2
NM_001145661.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%).
Absent from gnomAD v2.1 (exomes)gnomAD v4.1 (exomes)and gnomAD-Canada v1.0 (genomes).
✓
PP3
supporting
Pathogenic
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.
REVEL score 0.952 (deleterious). BayesDel score 0.604845 (deleterious). SpliceAI max delta 0.00 (no cryptic splice effectconsistent with computational assessment focused on missense impact).
Assessed · not applied
Pathogenic
PS1
Requires a different amino acid change at the same residue previously established as pathogenic.
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.
PS4
No case-control or prevalence data comparing variant frequency in affected vs.
PM1
The variant lies within the ZF1 domain of GATA2, which is a critical functional domain for DNA binding and transcriptional regulation.
PP1
No segregation data are available for this variant.
PP2
HCI prior gene-level constraint score is not available for GATA2.
PP4
No patient phenotype or clinical information is available for this case.
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).
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from all gnomAD databases.
BS2
No data on observation of this variant in healthy adult individuals in the absence of disease.
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.
BP4
Multiple in silico predictors support a deleterious effect: REVEL score 0.952 and BayesDel score 0.604845 both exceed thresholds for predicted pathogenicity.
BP6
This variant is classified as Uncertain Significance (not Benign or Likely Benign) by the sole ClinVar submitter.
N/A · 10
PVS1 · PS2 · PM5 · PM6 · BS4 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62003236, n = 29 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
22649106 ↗
GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.
ONCOKB