NM_001145661.1:c.856G>C

GATA2 · NP_001139133.1:p.(Ala286Pro) · NM_001145661.1

GRCh37: chr3:128204585 C>G · GRCh38: chr3:128485742 C>G

Gene: GATA2 Transcript: NM_001145661.1

Final call

VUS

PM2 supporting

Variant details

Gene

GATA2

Transcript

NM_001145661.1

Protein

NP_001139133.1:p.(Ala286Pro)

gnomAD AF

6.196808148059098e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The GATA2 c.856G>C (p.Ala286Pro) variant has been reported in ClinVar as a variant of uncertain significance with three clinical laboratory submissions.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (AF 6.19681e-07; 1/1613734 alleles), which supports rarity in population databases.

Computational evidence does not strongly support either a damaging or benign effect: SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL is 0.352, and BayesDel is -0.0703764.

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	GATA2 loss of function is an established disease mechanism, but this variant is a missense substitution rather than a nonsense, frameshift, or canonical ±1/2 splice variant, so the generic PVS1 framework does not apply.	pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No alternate nucleotide change producing the same p.Ala286Pro amino acid substitution was identified from the available evidence, so PS1 was not applied.
PS2	Not assessed	No confirmed de novo occurrence with parental relationship confirmation was identified for this variant, so PS2 was not applied.
PS3	Not assessed	No well-established functional study showing a damaging effect for p.Ala286Pro was identified in the available evidence, so PS3 was not applied.	oncokb
PS4	Not assessed	The available evidence does not provide a case-control enrichment analysis or sufficient independent affected-case count for this variant, so PS4 was not applied.	clinvar
PM1	Not met	Available hotspot review did not identify codon 286 as a statistically significant hotspot, so there is insufficient evidence that this variant lies in a well-established critical region without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (AF 6.19681e-07; 1/1613734 alleles; highest subpopulation AF 8.47469e-07), which is far below the 0.1% rarity threshold and supports rarity in population databases.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with pathogenic variants observed in trans, and the available evidence does not support use of a recessive framework for this GATA2 assessment.	pvs1_gene_context
PM4	N/A	This variant is a missense substitution and does not cause a protein length change or in-frame insertion/deletion, so PM4 does not apply.
PM5	N/A	The available PM5 review could not safely confirm that classic same-residue PM5 logic should be used for this case, and no validated same-residue pathogenic comparator was established, so PM5 was not applied.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not applied.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.
PP2	Not assessed	Available evidence does not establish a gene-level missense-specific constraint or a validated missense-prone mechanism at this residue sufficient to apply PP2.
PP3	Not met	Computational evidence is not strong enough to support a damaging prediction. SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL is 0.352, and BayesDel is -0.0703764, so the available in silico results do not meet a strong deleterious threshold for PP3.	spliceai revel bayesdel
PP4	Not assessed	No patient phenotype, laboratory phenotype, or disease-specific clinical presentation data were provided for this variant, so PP4 was not applied.
PP5	Not assessed	Although this variant is present in ClinVar, the available record does not provide an independent reputable-source assertion that can be used here for PP5.	clinvar
BA1	Not met	The observed population frequency is far below the 1% benign stand-alone threshold. In gnomAD v4.1 the total AF is 6.19681e-07, so BA1 is not met.	gnomad_v4
BS1	Not met	The observed population frequency is far below the 0.3% threshold typically used for BS1. In gnomAD v4.1 the total AF is 6.19681e-07, so BS1 is not met.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped healthy adult individuals at a level sufficient for BS2.	gnomad_v4
BS3	Not assessed	No well-established functional study showing normal protein function for p.Ala286Pro was identified, so BS3 was not applied.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not applied.
BP1	Not assessed	Available evidence is insufficient to conclude that missense variation in GATA2 is consistently less likely to be disease-causing than truncating variation, so BP1 was not applied.	pvs1_gene_context
BP2	Not assessed	No phase data or second-variant data were identified for this case, so BP2 was not applied.
BP3	N/A	This variant is not an in-frame insertion/deletion in a repetitive region, so BP3 does not apply.
BP4	Not met	Computational evidence does not provide sufficiently strong benign support. SpliceAI predicts no significant splice effect, but REVEL at 0.352 and BayesDel at -0.0703764 do not establish a clearly benign missense profile, so BP4 was not applied.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or independent cause for the phenotype was provided, so BP5 was not applied.
BP6	Not assessed	The available evidence does not provide an independent reputable-source benign classification that can be used here for BP6.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or intronic variant without predicted splice impact, so BP7 does not apply.	spliceai

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