NM_001145661.1:c.710G>A

GATA2 · NP_001139133.1:p.(Gly237Asp) · NM_001145661.1

GRCh37: chr3:128204731 C>T · GRCh38: chr3:128485888 C>T

Gene: GATA2 Transcript: NM_001145661.1

Final call

Benign

BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

GATA2

Transcript

NM_001145661.1

Protein

NP_001139133.1:p.(Gly237Asp)

gnomAD AF

0.0015421065088170823 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001145661.1:c.710G>A (p.Gly237Asp) in GATA2 is classified as Benign based on generic ACMG/AMP 2015 criteria.

This variant is present in gnomAD v2.1 at an allele frequency of 0.366% (1033/282138 alleles, including 17 homozygotes), exceeding the BS1 threshold of 0.3% for a rare dominant disorder.

Seventeen homozygous individuals are observed in gnomAD v2.1 (37 in gnomAD v4.1). Homozygosity for a variant in a gene causing a highly penetrant dominant disorder (GATA2 deficiency) is strong evidence of a benign effect (BS2).

Multiple in silico predictors support a benign interpretation: SpliceAI predicts no splice impact (max delta 0.00), REVEL score is 0.401 (below 0.5 threshold), and BayesDel score is -0.00217913 (benign range) (BP4).

Eight clinical laboratories in ClinVar classify this variant as Likely benign (4) or Benign (4), consistent with a benign interpretation (BP6).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Missense substitution (c.710G>A, p.Gly237Asp) does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus. PVS1 is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at the same amino acid residue (Gly237) resulting in a known pathogenic variant. No same-residue comparator variants were identified.	pm5_candidates
PS2	Not assessed	No de novo data available for this variant. No publications or ClinVar submissions report de novo occurrence.
PS3	Not met	No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence for this specific variant. No publications with functional data for NM_001145661.1:c.710G>A were found.	oncokb
PS4	Not met	The variant is present at 0.366% total allele frequency in gnomAD v2.1, which is inconsistent with a rare pathogenic variant. No case-control studies demonstrating enrichment in affected individuals were identified.	gnomad_v2 gnomad_v4
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Likely benign (4 laboratories) and Benign (4 laboratories). None of the associated PMIDs mention this specific variant.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Additionally, the high population frequency in the Finnish population (3.76% AF, 17 homozygotes) is inconsistent with a critical functional domain intolerant to benign variation.	gnomad_v2
PM2	Not met	Variant is present in gnomAD v2.1 at total allele frequency 0.366% (1033/282138 alleles), exceeding the 0.1% PM2 threshold for rarity. This variant is not absent from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no comparator pathogenic missense variants at Gly237 were identified in candidate harvesting.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant. No publications or ClinVar submissions report de novo occurrence.
PP1	Not assessed	No co-segregation data available for this variant.
PP2	Not met	Although GATA2 missense variants are a known disease mechanism in GATA2 deficiency syndrome, this specific variant is present at high population frequency (3.76% in Finnish, 17 homozygotes), which is incompatible with a pathogenic missense variant in a dominant disorder gene.	gnomad_v2
PP3	Not met	Multiple in silico predictors suggest no damaging effect: REVEL score 0.401 (below 0.5 threshold), BayesDel score -0.00217913 (benign range), SpliceAI max delta 0.00 (no predicted splice impact). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype information available to assess phenotypic specificity.
PP5	Not met	ClinVar reports this variant as Likely benign (4 clinical laboratories) and Benign (4 clinical laboratories). No reputable source reports it as pathogenic. The ClinVar-associated PMIDs (25741868, 32171751, 20963938, 33226740) do not mention this variant.	clinvar
BA1	Not met	Total allele frequency in gnomAD v2.1 is 0.366%, below the 1% BA1 threshold. Although the Finnish subpopulation AF is 3.76%, BA1 uses the overall population frequency.	gnomad_v2
BS1	Met	The variant has a total allele frequency of 0.366% (1033/282138 alleles) in gnomAD v2.1, which exceeds the 0.3% BS1 threshold. This frequency is greater than expected for GATA2 deficiency, a rare dominant disorder.	gnomad_v2 gnomad_v4
BS2	Met	Seventeen homozygotes are observed in gnomAD v2.1 (37 in gnomAD v4.1). GATA2 deficiency is a dominant disorder with high penetrance; the presence of homozygous individuals in a population database is incompatible with a pathogenic variant in this gene.	gnomad_v2 gnomad_v4
BS3	Not met	No variant-specific well-established functional studies demonstrating no damaging effect were identified. In silico evidence is addressed under BP4.
BS4	Not assessed	No segregation data available to assess lack of co-segregation with disease.
BP1	Not met	GATA2 deficiency is caused by both missense and truncating variants. Missense is a recognized pathogenic mechanism in this gene; BP1 is only applicable when a gene's disease mechanism is exclusively through truncating variants.	pvs1_gene_context
BP2	Not assessed	No data on whether this variant has been observed in trans with a known pathogenic GATA2 variant.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a repetitive region.
BP4	Met	Multiple computational predictors suggest no impact: SpliceAI max delta 0.00 (no predicted splice alteration), REVEL score 0.401 (below 0.5 threshold for predicted damaging), and BayesDel score -0.00217913 (in the benign range).	spliceai revel bayesdel
BP5	Not assessed	No information on whether this variant has been observed in cases with an alternate molecular basis for disease.
BP6	Met	Eight clinical laboratory submissions in ClinVar (ID 343139) classify this variant as Likely benign (4 laboratories) or Benign (4 laboratories). Although review status is 'criteria provided, single submitter' per submission, the consensus across multiple independent clinical laboratories supports a benign interpretation.	clinvar
BP7	N/A	This is a missense variant (c.710G>A, p.Gly237Asp), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice effect.
PM3	N/A	GATA2 deficiency is an autosomal dominant disorder; PM3 (detection in trans with a pathogenic variant) is applicable only to recessive disorders.
PM4	N/A	This is a substitution variant, not a nonstop or in-frame insertion/deletion. PM4 applies only to protein length-altering variants.

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