CEBPA c.2T>A, p.Met1?
NM_004364.3:c.2T>A
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:c.2T>A
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 is functionally characterized as a truncating mutation in the N-terminal region, leading to the production of the CEBPA p30 isoform. This isoform is associated with oncogenic activity in acute myeloid leukemia. Functional studies demonstrate that the CEBPA p30 isoform can bind gene promoters and repress gene expression independently of the full-length CEBPA p42 isoform. Additionally, in vitro studies show a switch-of-function effect, with the CEBPA p30 isoform upregulating UBC9 expression, which in turn downregulates the CEBPA p42 isoform through sumoylation. These findings support a damaging effect of the variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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 indicates that while it alters the initiation codon (c.2T>A), the transcript details are unknown and the pipeline explicitly states that PVS1 is not applicable or not evaluated. Therefore, this criterion is not applied.
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 caused by a different nucleotide change'. The evidence for this variant does not demonstrate that the same amino acid change has been previously established as pathogenic via a different nucleotide change. 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 supporting a de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing guidelines, 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 functional studies characterized the CEBPA M1 variant as a truncating mutation leading to the production of the CEBPA p30 isoform, which is associated with oncogenic activity in acute myeloid leukemia. The studies demonstrate altered promoter binding, transcriptional repression independent of the full-length isoform, and a switch-of-function effect. Therefore, this criterion is applied at Strong strength.
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 include any data on increased prevalence in affected individuals; in fact, it is absent in population databases without providing case-control enrichment. 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 does not indicate that the variant is in a mutational hot spot or a critical functional domain independent of other data. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to Standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)' as supported by population database data. The evidence for this variant shows that it is absent from gnomAD and other population control databases. Therefore, this criterion is applied at Moderate strength.
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)'. There is no evidence indicating that this variant 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 indicate an in-frame insertion/deletion or stop-loss change. 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 variant in question is not a missense variant in this context and there is no evidence for such a scenario. 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'. There is no evidence suggesting a de novo occurrence for this variant. 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'. The evidence does not include any segregation data supporting co-segregation of this variant with disease. 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 variant in question is not assessed as a typical missense variant in this scenario, and there is no evidence provided to support PP2. 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/gene product'. The evidence for this variant indicates that multiple in silico tools did not predict a deleterious effect, and SpliceAI analysis showed no impact on splicing. 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 is highly specific for a disease with a single genetic etiology'. There is no phenotype or family history data provided that is highly specific for a CEBPA-related disease in the context of this variant. 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'. There is no reputable external source reporting this variant as pathogenic 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 MAF of 0% in population databases, which does not meet the BA1 threshold. 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 variant is absent from controls and does not have a high allele frequency. 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; hence, BS2 is not applicable. 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 functional studies provided demonstrate a damaging effect through the production of the CEBPA p30 isoform with oncogenic properties. 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'. No segregation data has been provided, and thus, there is no basis to apply BS4. 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'. As this is not evaluated strictly as a missense variant, or where this context is not applicable to CEBPA, the evidence does not support applying BP1. 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 to indicate that this variant is observed 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 variant is not described as an in-frame indel within 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'. The evidence for this variant indicates that in silico prediction tools were insufficient to predict a damaging effect and SpliceAI analysis returned a score of 0, suggesting no predicted impact on splicing. 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 for another molecular basis for disease 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'. No such reputable report is available for 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'. This variant is not described as a synonymous variant and the evidence does not support BP7. Therefore, this criterion is not applied.