GATA2 c.230-3C>G, p.?
NM_001145661.1:c.230-3C>G
Variant of Uncertain Significance (VUS)
Variant of Uncertain Significance due to moderate evidence for absence in population databases (PM2) and supporting computational splicing evidence (PP3), with insufficient data for additional criteria.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
GATA2
Transcript
NM_001145661.2
Total Exons
7
Strand
Reverse (−)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001145661.1 | Alternative | 7 exons | Reverse |
Variant Details
HGVS Notation
NM_001145661.1:c.230-3C>G
Protein Change
?
Location
Exon 3
(Exon 3 of 7)
5'Exon Structure (7 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001145661.2
Genome Browser
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HGVS InputNM_001145661:c.230-3C>G
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.09
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion)"; The evidence for this variant shows: it is intronic at position -3, not affecting canonical ±1 or ±2 splice sites; Therefore, this criterion is not applied because the variant does not create a null effect as per rule.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant but caused by a different nucleotide change"; The evidence for this variant shows: it is intronic with no amino acid change; Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history"; The evidence for this variant shows: de novo status is unknown; Therefore, this criterion is not applied because de novo status cannot be determined.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product"; The evidence for this variant shows: no functional studies have been performed; Therefore, this criterion is not applied because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls"; The evidence for this variant shows: no case-control or prevalence data are available; Therefore, this criterion is not applied because prevalence information is absent.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation"; The evidence for this variant shows: it is intronic outside any known hotspot or functional domain; Therefore, this criterion is not applied because the variant location does not meet the rule.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)"; The evidence for this variant shows: it is not present in population databases including gnomAD; Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant"; The evidence for this variant shows: GATA2-associated disease is dominant and no trans variant is reported; Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants"; The evidence for this variant shows: it is an intronic substitution with no effect on protein length; Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen"; The evidence for this variant shows: it is not a missense variant; Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity"; The evidence for this variant shows: de novo status is unknown; Therefore, this criterion is not applied because de novo status cannot be assumed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members"; The evidence for this variant shows: no segregation data are available; Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease"; The evidence for this variant shows: it is not a missense variant; Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (e.g., conservation, splicing impact)"; The evidence for this variant shows: SpliceAI predicts moderate acceptor loss (score 0.59) and other algorithms indicate potential splicing impact; Therefore, this criterion is applied at Supporting strength because computational evidence supports a deleterious splicing effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology"; The evidence for this variant shows: no detailed phenotype or family history has been provided; Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence"; The evidence for this variant shows: no reputable source reports this variant; Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder"; The evidence for this variant shows: allele frequency is 0% in gnomAD; Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder"; The evidence for this variant shows: allele frequency is 0%; Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age"; The evidence for this variant shows: no data on healthy adult observations; Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing"; The evidence for this variant shows: no functional studies are available; Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members"; The evidence for this variant shows: no family segregation data are available; Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease"; The evidence for this variant shows: it is an intronic variant; Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant"; The evidence for this variant shows: no such observations; Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function"; The evidence for this variant shows: it is a single-nucleotide intronic substitution; Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product"; The evidence for this variant shows: computational predictions are mixed with some algorithms indicating potential splicing impact; Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease"; The evidence for this variant shows: no such case has been reported; Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence"; The evidence for this variant shows: no reputable source reports this variant; Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing"; The evidence for this variant shows: it is an intronic variant, not a synonymous exonic change; Therefore, this criterion is not applied.