CEBPA c.-90C>T, p.?
NM_004364.3:c.-90C>T
Variant of Uncertain Significance (VUS)
The c.-90C>T variant in CEBPA is classified as VUS. Only PM2 (Moderate) and BP4 (Supporting) apply, indicating rarity and benign computational predictions but insufficient evidence to reach benign or pathogenic thresholds.
ACMG/AMP Criteria Applied
PM2
BP4
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.-90C>T
Protein Change
?
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
Genome Browser
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HGVS InputNM_004364:c.-90C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00989%
Rare
Highest in Population
European (non-Finnish)
0.0199%
Low Frequency
Global: 0.00989%
European (non-Finnish): 0.0199%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 30320Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00989%, 3/30320 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0199%, 3/15088 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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
Functional Summary
The CEBPA -90c>T variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.22
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 is a known mechanism of disease." The evidence for this variant shows: "NM_004364.3:c.-90C>T is located in the 5′ UTR, not predicted to cause a null effect or loss of function." Therefore, this criterion is not applied because the variant does not introduce a null effect.
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 regardless of nucleotide change." The evidence for this variant shows: "No amino acid change (5′ UTR variant)." Therefore, this criterion is not applied because there is no protein 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: "No data on de novo status." Therefore, this criterion is not applied due to absence of de novo evidence.
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." The evidence for this variant shows: "No functional studies have been performed for c.-90C>T in CEBPA." Therefore, this criterion is not applied because functional evidence is 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 patient prevalence data available." Therefore, this criterion is not applied due to absence of case frequency data.
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: "Position -90 in the 5′ UTR is not a known hotspot or functional domain." Therefore, this criterion is not applied because the location is not within a recognized functional region.
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: "MAF = 0.00989% in gnomAD with no homozygotes; extremely rare." Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
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 shows: "No evidence of occurrence in trans with a pathogenic variant; CEBPA disease mechanism is not recessive." 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: "No change to protein length (non-coding UTR variant)." 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: "No missense or amino acid change." 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: "No de novo data at all." 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 for this variant shows: "No family segregation data 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." The evidence for this variant shows: "Variant is non-coding; not a missense change." 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." The evidence for this variant shows: "In silico predictors (CADD=0.22; SpliceAI=0.03) do not support deleterious impact." Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: "No phenotype or clinical data 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 without accessible evidence." The evidence for this variant shows: "ClinVar reports Uncertain Significance; no pathogenic report." 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: "MAF = 0.00989%, which is below the BA1 threshold (>5%)." 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: "MAF is still extremely low (<0.1%), not exceeding disorder-specific thresholds." 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 adult individuals for a dominant disorder with full penetrance." The evidence for this variant shows: "No curated healthy adult observations reported." 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." The evidence for this variant shows: "No functional studies 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 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 loss of function causes disease." The evidence for this variant shows: "Non-coding UTR change, not missense." 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 cis/trans phasing data." 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: "Not an in-frame indel; single nucleotide variant in UTR." 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." The evidence for this variant shows: "CADD score=0.22 (below threshold), SpliceAI max score=0.03 (no splicing impact)." Therefore, this criterion is applied at Supporting strength because computational tools predict no functional impact.
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 case reports with alternate genetic findings." 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 without accessible evidence." The evidence for this variant shows: "No such benign classification 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 shows: "Not a synonymous coding change, it is in 5′ UTR." Therefore, this criterion is not applied.