chr19-33302163-G-C
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004364.5(CEBPA):āc.252C>Gā(p.His84Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000183 in 1,472,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000017 ( 0 hom. )
Consequence
CEBPA
NM_004364.5 missense
NM_004364.5 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 4.25
Genes affected
CEBPA (HGNC:1833): (CCAAT enhancer binding protein alpha) This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain and recognizes the CCAAT motif in the promoters of target genes. The encoded protein functions in homodimers and also heterodimers with CCAAT/enhancer-binding proteins beta and gamma. Activity of this protein can modulate the expression of genes involved in cell cycle regulation as well as in body weight homeostasis. Mutation of this gene is associated with acute myeloid leukemia. The use of alternative in-frame non-AUG (GUG) and AUG start codons results in protein isoforms with different lengths. Differential translation initiation is mediated by an out-of-frame, upstream open reading frame which is located between the GUG and the first AUG start codons. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.41409647).
BS2
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CEBPA | NM_004364.5 | c.252C>G | p.His84Gln | missense_variant | 1/1 | ENST00000498907.3 | NP_004355.2 | |
CEBPA | NM_001287424.2 | c.357C>G | p.His119Gln | missense_variant | 1/1 | NP_001274353.1 | ||
CEBPA | NM_001287435.2 | c.210C>G | p.His70Gln | missense_variant | 1/1 | NP_001274364.1 | ||
CEBPA | NM_001285829.2 | c.-106C>G | 5_prime_UTR_variant | 1/1 | NP_001272758.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CEBPA | ENST00000498907.3 | c.252C>G | p.His84Gln | missense_variant | 1/1 | NM_004364.5 | ENSP00000427514 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151382Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000174 AC: 23AN: 1321438Hom.: 0 Cov.: 33 AF XY: 0.0000199 AC XY: 13AN XY: 651674
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GnomAD4 genome AF: 0.0000264 AC: 4AN: 151382Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3AN XY: 73906
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acute myeloid leukemia Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 07, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 22, 2023 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 84 of the CEBPA protein (p.His84Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 239920). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEBPA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of solvent accessibility (P = 0.0374);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at