Variant classification summary

NM_001145661.1:c.953C>T

GATA2 · NP_001139133.1:p.(Ala318Val) · NM_001145661.1

GRCh37: chr3:128202767 G>A · GRCh38: chr3:128483924 G>A

Gene: GATA2 Transcript: NM_001145661.1

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

GATA2

Transcript

NM_001145661.1

Protein

NP_001139133.1:p.(Ala318Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

This variant is classified as Uncertain Significance in ClinVar (1 clinical laboratory, criteria provided, single submitter). No expert panel classification is available.

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework
PS1	Not assessed	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.
PS2	N/A	No 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.
PS3	Not assessed	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.
PS4	Not assessed	No case-control or prevalence data comparing variant frequency in affected vs. unaffected cohorts are available.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 sequence variant interpretation framework (PMID:25741868).
PM1	Not met	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.	PMID:22649106
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	N/A	No de novo observation is available for this variant. No parentage data or de novo reports were identified in ClinVar or the literature reviewed.
PP1	Not assessed	No segregation data are available for this variant. No family studies with co-segregation of this variant and disease phenotype were identified.
PP2	Not assessed	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.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 1% in any population database.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all gnomAD databases. BS1 requires an allele frequency > 0.3% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	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.
BS3	Not met	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.	PMID:22649106
BS4	N/A	No segregation data are available to assess lack of segregation with disease. No family studies involving this variant were identified.
BP1	N/A	GATA2 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.	pvs1_gene_context
BP2	N/A	No phase data are available to assess observation in trans with a pathogenic variant. No cis/trans phase information was identified for this variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_001145661.1:c.953C>T is a missense substitution, not an in-frame indel.
BP4	Not met	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.	revel bayesdel
BP5	N/A	No 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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

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