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CEBPAc.47_48delinsAUncertain significance
Print report
Variant interpretation report

CEBPA c.47_48delinsA, p.(Ser16LysfsTer144)

NM_004364.3:c.47_48delinsA NP_004355.2:p.(Ser16LysfsTer144) View identifiers
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.

About CEBPA

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Frameshift variant NM_004364.3:c.47_48delinsA (p.Ser16LysfsTer144) in exon 1 of CEBPA, a gene where loss-of-function is an established mechanism for autosomal dominant familial acute myeloid leukemia predisposition. The variant is predicted to cause premature termination at codon 159, ablating expression of the full-length p42 isoform. Germline loss-of-function disease mechanism confirmed by literature review supporting CEBPA as a germline predisposition gene (WHO 5th edition myeloid neoplasm classification). Assessed under ClinGen SVI PVS1 framework (PMC6185798).

PM2Supporting
PM2 · supporting

Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015 rules, PM2 is met at supporting strength (allele frequency <0.1%).

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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 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.

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
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 6 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 (Very Strong): NM_004364.3:c.47_48delinsA is a frameshift null variant in CEBPA, a gene where loss-of-function is an established mechanism for autosomal dominant familial AML predisposition. The variant is predicted to produce p.Ser16LysfsTer144, ablating expression of the full-length p42 isoform. Assessed under ClinGen SVI PVS1 framework (PMC6185798).

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.

Classification: Variant of Uncertain Significance (VUS). Met criteria: PVS1 (Very Strong) + PM2 (Supporting). Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), 1 Very Strong + 1 Supporting does not reach the threshold for Likely Pathogenic (which requires at least 1 Very Strong + 1 Moderate, or 1 Strong + 2 Supporting). While the variant is strongly suggestive of pathogenicity based on its molecular consequence and absence from population databases, additional evidence (functional data, segregation, case observations, or ClinVar classification by an expert panel) would be needed to upgrade to Likely Pathogenic.

Met · 2

PVS1 Very strongFrameshift variant NM_004364.3:c.47_48delinsA (p.Ser16LysfsTer144) in exon 1 of CEBPA, a gene where loss-of-function is an established mechanism for autosomal dominant familial acute myeloid leukemia predisposition. The variant is predicted to cause premature termination at codon 159, ablating expression of the full-length p42 isoform. Germline loss-of-function disease mechanism confirmed by literature review supporting CEBPA as a germline predisposition gene (WHO 5th edition myeloid neoplasm classification). Assessed under ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Frameshift null variant at codon 16 of 359 in a gene with established germline loss-of-function disease mechanism
  • Variant predicted to produce p.Ser16LysfsTer144
  • abolishing full-length p42 CEBPA isoform expression
  • CEBPA germline LoF is associated with familial AML predisposition per WHO classification
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingVariant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015 rules, PM2 is met at supporting strength (allele frequency <0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PM1 Variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org. Although CEBPA N-terminal mutations cluster in AML, the exact residue (Ser16) is not flagged as a significant hotspot residue. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org analysis: residue not statistically significant
  • exact variant not listed as hotspot
PP3 SpliceAI predicts no splice-altering effect (max delta score = 0.00). REVEL and BayesDel are not applicable to indels. No in silico evidence supports a deleterious effect beyond the established truncation mechanism. For a frameshift variant, the primary pathogenic mechanism is protein truncation, which is already captured by PVS1 and should not be double-counted with PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no cryptic splice site creation or disruption predicted
Sources
spliceai ↗
PP5 Variant is absent from ClinVar and has not been classified by any germline diagnostic laboratory or expert panel. OncoKB classifies this variant as Likely Oncogenic, but this is a somatic oncology annotation and does not constitute a reputable germline variant classification source for PP5 under ACMG/AMP guidelines. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no germline classification available
  • OncoKB: Likely Oncogenic (somatic context
  • not germline ACMG classification)
Sources
clinvar ↗oncokb ↗
BA1 Variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0% across all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Variant is absent from all population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0% across all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP6 Variant is absent from ClinVar and has not been classified as benign or likely benign by any reputable source. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation data available
PS3 Five papers on N-terminal CEBPA mutations and p30 isoform function were reviewed in full text or abstract. None mention the specific variant NM_004364.3:c.47_48delinsA or p.Ser16LysfsTer144. While these papers demonstrate that N-terminal CEBPA frameshifts leading to p30 expression are pathogenic in somatic AML, no variant-specific functional data exist for this exact variant. Details ▾Hide ▴
Evidence considered
  • Five publications reviewed (PMID:17242690
  • 17671234
  • 20884804
  • 31309149
  • 31867767) describe functional effects of N-terminal CEBPA mutations and p30 isoform but do not contain variant-specific data for c.47_48delinsA
Still missing
  • No variant-specific functional assays (e.g.
  • luciferase reporter
  • Western blot
  • differentiation assay) for NM_004364.3:c.47_48delinsA
PS4 No case-control data or prevalence comparison available for this variant. Details ▾Hide ▴
Still missing
  • No case-control studies or cohort prevalence data for this specific variant
PM6 No de novo data with or without confirmed maternity/paternity available for this variant. Details ▾Hide ▴
Still missing
  • No de novo observations reported for this variant
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient phenotype data available to assess specificity of clinical presentation. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical data provided
BS2 No data on observation of this variant in healthy adults available. BS2 requires a variant to be observed in a healthy adult individual for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No data on variant presence in healthy adult controls beyond gnomAD population-level absence
BS3 Five papers on CEBPA N-terminal mutations were reviewed (full text for PMID:31309149 and PMID:31867767; abstracts for PMID:17242690, 17671234, 20884804). All describe N-terminal frameshift mutations as pathogenic/likely pathogenic in AML via p30-mediated mechanisms. None contain variant-specific functional evidence showing a benign effect for this variant. BS3 requires well-established functional studies showing no damaging effect, which is not applicable here as the available functional literature supports a deleterious role for this class of mutations. Details ▾Hide ▴
Evidence considered
  • Five publications reviewed describe N-terminal CEBPA mutations as functionally deleterious
  • no variant-specific benign functional evidence exists
BS4 No segregation data available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data on observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
  • No data on phase or co-occurrence with other CEBPA variants
BP5 No data on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on variant presence in individuals with an alternative molecular diagnosis
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change as a previously established pathogenic missense variant. This variant is a frameshift, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a frameshift and does not qualify for PM4. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a known pathogenic missense change at the same residue. This variant is a frameshift and cannot be evaluated under PM5. Automated PM5 candidate harvesting confirmed: unable to establish same-residue comparator semantics. Details ▾Hide ▴
Evidence considered
  • Automated PM5 candidate search found no eligible same-residue comparators
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. This variant is a truncating (frameshift) variant, not a missense. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. This is a frameshift variant with a clear protein-truncating effect; in silico splicing predictions (SpliceAI delta = 0.00) do not address the primary mechanism of protein truncation and are not sufficient to apply BP4. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not applicable to frameshift variants. PS5 evaluates a different nucleotide change at the same position as a known pathogenic variant, which is a missense-only concept. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CEBPA
Transcript
NM_004364.3
Coding (HGVS c.)
NM_004364.3:c.47_48delinsA
Protein (HGVS p.)
NP_004355.2:p.(Ser16LysfsTer144)
GRCh38
chr19:33302367 GC>T
GRCh37
chr19:33793273 GC>T

Gene diagram

Every interpreted variant in CEBPA, mapped onto the exon structure of NM_004364.3. Select a row to find it on the plot.

CEBPANM_004364.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -499 bp
0.000
SpliceAI acceptor gainat -76 bp
0.000
SpliceAI donor lossat +153 bp
0.000
SpliceAI donor gainat -168 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no splice-altering effect (max delta score = 0.00). REVEL and BayesDel are not applicable to indels. No in silico evidence supports a deleterious effect beyond the established truncation mechanism. For a frameshift variant, the primary pathogenic mechanism is protein truncation, which is already captured by PVS1 and should not be double-counted with PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no cryptic splice site creation or disruption predicted
Sources
spliceai ↗
BP4 N/ABP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. This is a frameshift variant with a clear protein-truncating effect; in silico splicing predictions (SpliceAI delta = 0.00) do not address the primary mechanism of protein truncation and are not sufficient to apply BP4. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

5 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

  • C/EBPalphap30 plays transcriptional regulatory roles distinct from C/EBPalphap42.
    Describes transcriptional regulatory roles of C/EBPalpha p30 isoform distinct from full-length p42. Reports that p30 specifically inhibits a unique set of genes including MPP11, p84N5, and SMYD2. The paper discusses C/EBPalpha isoforms and their differential gene regulatory functions but does not report any specific patient variant.
    Does not name this variant
    PMID 17242690 ↗
  • Target proteins of C/EBPalphap30 in AML: C/EBPalphap30 enhances sumoylation of C/EBPalphap42 via up-regulation of Ubc9.
    Identifies Ubc9 as a target protein of C/EBPalpha p30 in AML. Demonstrates that p30 enhances sumoylation of p42 via up-regulation of Ubc9, leading to decreased p42/p30 ratio. Discusses CEBPA N-terminal mutations in AML generally but does not reference any specific variant.
    Does not name this variant
    PMID 17671234 ↗
  • Two types of C/EBP&#x3b1; mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models.
    Describes two types of CEBPA mutations in AML: N-terminal mutations expressing dominant-negative p30 and C-terminal bZIP domain mutations. Reports that N-terminal CEBPA mutations are observed in AML after myelodysplasia. Discusses mutation classes but does not report any specific variant identifiers.
    Does not name this variant
    PMID 20884804 ↗
  • Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.
    Demonstrates that mutant CEBPA-p30 directly drives expression of CD73 (encoded by NT5E) via a leukemia-specific enhancer in CEBPA-mutant AML. Uses ChIP-seq, RNA-seq, and CRISPRi in a murine Cebpa Lp30 model and human patient samples. Shows that N-terminal CEBPA mutations result in p30-specific enhancer binding and activation of target genes including CD73, promoting leukemic growth via A2AR signaling. Full text reviewed; no specific variant identifiers (c.47_48delinsA, S16Kfs*144) found.
    Does not name this variant
    PMID 31309149 ↗
  • Gain-of-Function Effects of N-Terminal CEBPA Mutations in Acute Myeloid Leukemia.
    Review article on gain-of-function effects of N-terminal CEBPA mutations in AML. Summarizes evidence that the C/EBPalpha p30 isoform (produced by N-terminal frameshift mutations) retains active gene regulatory capacity, preferentially interacts with the MLL1 complex, and binds low-affinity CEBPA motifs at primed enhancers. Full text reviewed; discusses N-terminal frameshift mutations as a class with reference to COSMIC database mutation distribution (Figure 1) but does not list or reference specific variant identifiers such as c.47_48delinsA.
    Does not name this variant
    PMID 31867767 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

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.