chr19-33301394-T-C
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_004364.5(CEBPA):āc.1021A>Gā(p.Ile341Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 1,609,812 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 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.000076 ( 0 hom. )
Consequence
CEBPA
NM_004364.5 missense
NM_004364.5 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 2.19
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 -4 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_004364.5
BP4
Computational evidence support a benign effect (MetaRNN=0.23638391).
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEBPA | NM_004364.5 | c.1021A>G | p.Ile341Val | missense_variant | 1/1 | ENST00000498907.3 | |
CEBPA | NM_001287424.2 | c.1126A>G | p.Ile376Val | missense_variant | 1/1 | ||
CEBPA | NM_001287435.2 | c.979A>G | p.Ile327Val | missense_variant | 1/1 | ||
CEBPA | NM_001285829.2 | c.664A>G | p.Ile222Val | missense_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEBPA | ENST00000498907.3 | c.1021A>G | p.Ile341Val | missense_variant | 1/1 | NM_004364.5 | P1 | ||
ENST00000587312.1 | n.116T>C | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000328 AC: 8AN: 244130Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133308
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GnomAD4 exome AF: 0.0000762 AC: 111AN: 1457586Hom.: 0 Cov.: 31 AF XY: 0.0000745 AC XY: 54AN XY: 725266
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ovarian cancer (PMID: 24448499); This variant is associated with the following publications: (PMID: 29025912, 21455213, 24448499) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 25, 2021 | - - |
Acute myeloid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the CEBPA protein (p.Ile341Val). This variant is present in population databases (rs372931505, gnomAD 0.008%). 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: 239918). 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
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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