NM_004364.5:c.51C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_004364.5(CEBPA):​c.51C>A​(p.Ser17Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000912 in 1,315,464 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S17G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

4
2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.31

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.39336506).
BP6
Variant 19-33302364-G-T is Benign according to our data. Variant chr19-33302364-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456689.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEBPANM_004364.5 linkc.51C>A p.Ser17Arg missense_variant Exon 1 of 1 ENST00000498907.3 NP_004355.2 P49715-1
CEBPANM_001287424.2 linkc.156C>A p.Ser52Arg missense_variant Exon 1 of 1 NP_001274353.1 P49715-4
CEBPANM_001287435.2 linkc.9C>A p.Ser3Arg missense_variant Exon 1 of 1 NP_001274364.1 P49715-2
CEBPANM_001285829.2 linkc.-307C>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.51C>A p.Ser17Arg missense_variant Exon 1 of 1 6 NM_004364.5 ENSP00000427514.1 P49715-1
CEBPA-DTENST00000718467.1 linkn.46+565G>T intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151424
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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
GnomAD2 exomes
AF:
0.0000909
AC:
1
AN:
10996
AF XY:
0.000181
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000581
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000945
AC:
11
AN:
1164040
Hom.:
0
Cov.:
32
AF XY:
0.0000107
AC XY:
6
AN XY:
562158
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
23160
American (AMR)
AF:
0.00
AC:
0
AN:
8588
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
15094
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26880
South Asian (SAS)
AF:
0.00
AC:
0
AN:
37178
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38102
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4274
European-Non Finnish (NFE)
AF:
0.00000934
AC:
9
AN:
964066
Other (OTH)
AF:
0.0000428
AC:
2
AN:
46698
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.457
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:
0.00000660
AC:
1
AN:
151424
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73934
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41332
American (AMR)
AF:
0.0000656
AC:
1
AN:
15234
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5088
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67812
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Acute myeloid leukemia Uncertain:1
Oct 28, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 17 of the CEBPA protein (p.Ser17Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 456689). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T
Eigen
Benign
0.072
Eigen_PC
Benign
0.029
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.58
T
M_CAP
Pathogenic
0.77
D
MetaRNN
Benign
0.39
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.7
L
PhyloP100
4.3
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.11
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.57
T
Polyphen
0.99
D
Vest4
0.44
MutPred
0.21
Gain of solvent accessibility (P = 0.0055);
MVP
0.33
ClinPred
0.64
D
GERP RS
1.8
PromoterAI
-0.040
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.6
Varity_R
0.18
gMVP
0.47
Mutation Taster
=70/30
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: rs1245499278; hg19: chr19-33793270; API