About GATA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GATA2 c.856G>C, p.(Ala286Pro)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
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; combination = 1 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
1 / 1,613,734 alleles
gnomAD v4.1: 1 / 1,613,734 alleles. Recorded AF 6.19681e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
28 criteria with recorded statuses: 1 met · 5 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Present once in gnomAD v4.1 at extremely low frequency.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review found no hotspot row for GATA2 A286.
Still missing
- A curated functional-domain source tied to this residue would be needed to revisit PM1.
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.352.
- BayesDel score -0.0703764.
Still missing
- Additional validated computational framework thresholds specific to GATA2 could refine this assessment.
Sources
BA1 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. Details ▾Hide ▴
BS1 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. Details ▾Hide ▴
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.352 is intermediate.
- BayesDel score is mildly negative but not sufficient alone for benign support.
Still missing
- A validated benign computational threshold framework specific to this context would be needed.
Sources
Not assessed · 16 · no assessment recorded
PS1 No alternate nucleotide change producing the same p.Ala286Pro amino acid substitution was identified from the available evidence, so PS1 was not applied. Details ▾Hide ▴
Still missing
- Confirm whether any other nucleotide substitution causing p.Ala286Pro has been reported and classified independently.
PS2 No confirmed de novo occurrence with parental relationship confirmation was identified for this variant, so PS2 was not applied. Details ▾Hide ▴
Still missing
- Trio-based testing with confirmed maternity and paternity would be needed.
PS3 No well-established functional study showing a damaging effect for p.Ala286Pro was identified in the available evidence, so PS3 was not applied. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Variant-specific functional assay data would be needed to assess protein effect.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- ClinVar contains submissions but does not establish statistical enrichment.
Still missing
- Published affected-case counts and a control comparison would be needed.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not applied. Details ▾Hide ▴
Still missing
- A reported sporadic case with incomplete parental confirmation would be needed.
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Still missing
- Family-level genotyping and phenotype data would be needed.
PP2 Available evidence does not establish a gene-level missense-specific constraint or a validated missense-prone mechanism at this residue sufficient to apply PP2. Details ▾Hide ▴
Still missing
- A gene-specific missense constraint framework would be needed.
PP4 No patient phenotype, laboratory phenotype, or disease-specific clinical presentation data were provided for this variant, so PP4 was not applied. Details ▾Hide ▴
Still missing
- Phenotypic data specific to the tested individual would be needed.
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification is uncertain significance with single-submitter review status.
Still missing
- An independently reviewable external assertion with supporting evidence would be needed.
Sources
BS2 No evidence was identified showing this variant in well-phenotyped healthy adult individuals at a level sufficient for BS2. Details ▾Hide ▴
Evidence considered
- Population database shows only one allele and no phenotyped healthy-carrier dataset for BS2 use.
Still missing
- Observation in multiple unaffected
- appropriately aged individuals would be needed.
Sources
BS3 No well-established functional study showing normal protein function for p.Ala286Pro was identified, so BS3 was not applied. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Variant-specific benign-supporting functional assay data would be needed.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Still missing
- Family studies with clear phenotype definitions and ages would be needed.
BP1 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. Details ▾Hide ▴
Evidence considered
- GATA2 loss of function is established
- but this alone does not justify BP1 for a missense variant.
Still missing
- A validated gene-specific framework addressing missense versus truncating mechanism would be needed.
Sources
pvs1_gene_context
BP2 No phase data or second-variant data were identified for this case, so BP2 was not applied. Details ▾Hide ▴
Still missing
- Phase information and any additional pathogenic variant data would be needed.
BP5 No alternate molecular diagnosis or independent cause for the phenotype was provided, so BP5 was not applied. Details ▾Hide ▴
Still missing
- Clinical context and other molecular findings would be needed.
BP6 The available evidence does not provide an independent reputable-source benign classification that can be used here for BP6. Details ▾Hide ▴
Evidence considered
- ClinVar lists uncertain significance rather than a benign assertion.
Still missing
- An independently reviewable benign external assertion would be needed.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AGATA2 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. Details ▾Hide ▴
Evidence considered
- Generic PVS1 gene gate is eligible for GATA2 loss-of-function variants.
- Variant-level PVS1 scaffold indicates this missense change is outside the default null-variant buckets.
Still missing
- Variant-specific RNA data would be needed only if a noncanonical splicing effect were later suspected.
Sources
pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 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. Details ▾Hide ▴
Evidence considered
- GATA2 disease context reviewed under dominant loss-of-function framework.
Sources
pvs1_gene_context
PM4 N/AThis variant is a missense substitution and does not cause a protein length change or in-frame insertion/deletion, so PM4 does not apply. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThe 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. Details ▾Hide ▴
Evidence considered
- PM5 artifact marked classic same-residue semantics as unconfirmed and skipped automatic harvesting.
Still missing
- If a gene-specific same-residue framework becomes available
- comparator variants could be reassessed.
Sources
pm5_candidates
BP3 N/AThis variant is not an in-frame insertion/deletion in a repetitive region, so BP3 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant rather than a synonymous or intronic variant without predicted splice impact, so BP7 does not apply. Details ▾Hide ▴
Identifiers
- Gene
- GATA2
- Transcript
- NM_001145661.1
- Coding (HGVS c.)
- NM_001145661.1:c.856G>C
- Protein (HGVS p.)
- NP_001139133.1:p.(Ala286Pro)
- GRCh38
- chr3:128485742 C>G
- GRCh37
- chr3:128204585 C>G
- ClinVar
- 934804
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in GATA2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,734 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,734 alleles · 0 hom
| European (non-Finnish)1 / 1,179,984 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19681e-07; MAF= 0.00006%, 1/1613734 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47469e-07; MAF= 0.00008%, 1/1179984 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.352
- BayesDel
- -0.070
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.352.
- BayesDel score -0.0703764.
Still missing
- Additional validated computational framework thresholds specific to GATA2 could refine this assessment.
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.352 is intermediate.
- BayesDel score is mildly negative but not sufficient alone for benign support.
Still missing
- A validated benign computational threshold framework specific to this context would be needed.
Sources
BP7 N/AThis is a missense variant rather than a synonymous or intronic variant without predicted splice impact, so BP7 does not apply. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.352. BayesDel score = -0.0703764.
12 paper records 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 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.No paper-specific finding is recorded.
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.No paper-specific finding is recorded.
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015No paper-specific finding is recorded.
-
PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.No paper-specific finding is recorded.
-
PMID 23169492 ↗The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.Fears R et al. · 2013No paper-specific finding is recorded.
-
PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014No paper-specific finding is recorded.
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012No paper-specific finding is recorded.
-
PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013No paper-specific finding is recorded.
-
PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.No paper-specific finding is recorded.
-
PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].No paper-specific finding is recorded.
-
PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,734 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 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/934804/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-128204585-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-128485742-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001145661.1%3Ac.8…
- OncoKB ↗www.oncokb.org/gene/GATA2/A286P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GATA2+c.856G%3EC
- 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
This variant is present in gnomAD v4.1 (AF= 6.19681e-07; MAF= 0.00006%, 1/1613734 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47469e-07; MAF= 0.00008%, 1/1179984 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 934804)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.352. BayesDel score = -0.0703764.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.