CEBPA c.1A>G, p.Met1?
NM_004364.3(CEBPA):c.1A>G
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
CEBPA
Transcript
NM_004364.5
MANE Select
Total Exons
1
Strand
Reverse (−)
Reference Sequence
NC_000019.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004364.2 | Alternative | 1 exons | Reverse |
| NM_004364.4 | RefSeq Select | 1 exons | Reverse |
| NM_004364.3 | Alternative | 1 exons | Reverse |
Variant Details
HGVS Notation
NM_004364.3(CEBPA):c.1A>G
Protein Change
M1?
Location
Exon 1
(Exon 1 of 1)
5'
Exon Structure (1 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_004364.5
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
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
Functional Studies
Summary
The CEBPA M1 variant results in a truncating mutation in the N-terminal region, producing the CEBPA p30 isoform. This isoform is functionally characterized by its ability to bind gene promoters and repress gene expression independently of the full-length CEBPA p42 isoform. In vitro studies demonstrate a switch-of-function, with the CEBPA p30 isoform upregulating UBC9 expression, leading to downregulation of the CEBPA p42 isoform via sumoylation. In vivo studies show that co-expression of the CEBPA p30 isoform with C-terminal mutations is oncogenic, contributing to leukemogenesis. This functional evidence supports a damaging effect of the variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.38
VCEP Guidelines
Applied ACMG/AMP Criteria
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 in a LoF gene)'. The evidence for this variant shows a change at the initiation codon (c.1A>G), but the effect is not straightforwardly equivalent to a null variant because alternative isoforms (e.g., resulting in the p30 isoform) are generated. Therefore, this criterion is not applied at any strength because the variant does not clearly meet the null variant definition required under PVS1.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but via a different nucleotide change'. The evidence for this variant does not indicate that the same amino acid change has been previously established as pathogenic by a different nucleotide substitution. Therefore, this criterion is not applied.
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'. There is no evidence in the provided data regarding a de novo occurrence with confirmed parentage. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing guidelines (as applied for PS3 in this evaluation), the rule/finding for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows that the CEBPA M1 change results in a truncating mutation in the N-terminal region producing the CEBPA p30 isoform. In vitro studies have demonstrated a switch-of-function effect, including upregulation of UBC9 and consequent downregulation of the full-length isoform via sumoylation, and in vivo studies indicate that co-expression with C-terminal mutations is oncogenic. Therefore, this criterion is applied at Strong strength because the functional studies are well established and clearly support a damaging effect.
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 does not provide data on an increased prevalence in affected individuals compared to controls. Therefore, this criterion is not applied.
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 does not specifically indicate that it is located in such a mutational hot spot or domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to Standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at an extremely low frequency if recessive)'. The evidence for this variant shows that it is absent from population databases (gnomAD) with a MAF of 0%. Therefore, this criterion is applied at Moderate strength because the variant is not present in control populations.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant does not provide any information indicating that it is detected in trans with another pathogenic variant. 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 does not suggest an in-frame deletion/insertion or stop-loss that changes the protein length in this manner. 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 does not indicate that a different pathogenic missense change at the same residue has been reported. 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 does not include any indication of a de novo occurrence. Therefore, this criterion is not applied.
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'. There is no evidence provided regarding segregation analysis in affected families. 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 does not provide supporting information that meets this definition as the computational predictions do not consistently support a deleterious impact. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
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'. The evidence for this variant shows a low CADD score (2.38) and SpliceAI analysis that predicts no impact on splicing, which do not support a deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The provided evidence does not include such phenotype or family history information. 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 does not include a reputable source claim with accessible evidence. 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 (based on population data)'. The evidence for this variant shows a frequency of 0% in population databases, so this criterion is not applicable. 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 it is absent from control databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. There is no evidence that this variant has been observed in healthy individuals of an appropriate age. 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 clearly shows a damaging effect via functional studies. 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'. There is no segregation data provided for this variant. 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 for which primarily truncating variants cause disease'. The evidence for this variant does not fit this scenario because the functional evidence supports a damaging effect through production of an alternative isoform rather than a simple benign missense change. 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'. There is no evidence that this variant is in trans or in cis with another pathogenic variant. 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 does not indicate an in-frame deletion/insertion in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to Standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (e.g., conservation, evolutionary, splicing impact)'. The evidence for this variant includes a low CADD score (2.38) and SpliceAI analysis with a score of 0 for splicing impact, indicating no predicted functional impact from a computational standpoint. Therefore, this criterion is applied at Supporting strength.
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'. There is no evidence suggesting that the disease is attributable to another molecular change in this case. 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 provided does not include any such report from a reputable source. 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 involves an initiation codon change rather than a synonymous change. Therefore, this criterion is not applied.