NM_004364.5:c.37C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004364.5(CEBPA):​c.37C>A​(p.Pro13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000612 in 1,306,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.12

Publications

1 publications found
Variant links:
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]
CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEBPANM_004364.5 linkc.37C>A p.Pro13Thr missense_variant Exon 1 of 1 ENST00000498907.3 NP_004355.2 P49715-1
CEBPANM_001287424.2 linkc.142C>A p.Pro48Thr missense_variant Exon 1 of 1 NP_001274353.1 P49715-4
CEBPANM_001287435.2 linkc.-6C>A 5_prime_UTR_variant Exon 1 of 1 NP_001274364.1 P49715-2
CEBPANM_001285829.2 linkc.-321C>A 5_prime_UTR_variant Exon 1 of 1 NP_001272758.1 P49715-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEBPAENST00000498907.3 linkc.37C>A p.Pro13Thr missense_variant Exon 1 of 1 6 NM_004364.5 ENSP00000427514.1 P49715-1
CEBPA-DTENST00000718467.1 linkn.46+579G>T intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.0000264
AC:
4
AN:
151440
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000968
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000346
AC:
4
AN:
1155348
Hom.:
0
Cov.:
32
AF XY:
0.00000180
AC XY:
1
AN XY:
556498
show subpopulations
African (AFR)
AF:
0.000173
AC:
4
AN:
23078
American (AMR)
AF:
0.00
AC:
0
AN:
8474
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14956
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26780
South Asian (SAS)
AF:
0.00
AC:
0
AN:
35180
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
37124
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
959338
Other (OTH)
AF:
0.00
AC:
0
AN:
46282
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000264
AC:
4
AN:
151440
Hom.:
0
Cov.:
32
AF XY:
0.0000406
AC XY:
3
AN XY:
73980
show subpopulations
African (AFR)
AF:
0.0000968
AC:
4
AN:
41334
American (AMR)
AF:
0.00
AC:
0
AN:
15226
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3460
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5092
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67804
Other (OTH)
AF:
0.00
AC:
0
AN:
2080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 28, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.P13T variant (also known as c.37C>A), located in coding exon 1 of the CEBPA gene, results from a C to A substitution at nucleotide position 37. The proline at codon 13 is replaced by threonine, an amino acid with highly similar properties. This variant was identified amongst 22,659 patients with hematological conditions, but germline origin was not confirmed (Hogg G et al. Cancer Genet, 2023 Nov;278-279:38-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1
Feb 12, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Acute myeloid leukemia Uncertain:1
Jan 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1396087). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the CEBPA protein (p.Pro13Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Benign
0.0041
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.97
D
MetaRNN
Uncertain
0.55
D
MetaSVM
Benign
-0.61
T
MutationAssessor
Uncertain
2.1
M
PhyloP100
6.1
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.23
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.023
D
Polyphen
1.0
D
Vest4
0.24
MutPred
0.21
Loss of catalytic residue at P13 (P = 0.0077);
MVP
0.59
ClinPred
0.98
D
GERP RS
4.1
PromoterAI
0.037
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.6
Varity_R
0.47
gMVP
0.55
Mutation Taster
=54/46
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs961496947; hg19: chr19-33793284; API