rs998501847

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004364.5(CEBPA):​c.547C>T​(p.Pro183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000529 in 1,324,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14944807).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CEBPANM_004364.5 linkuse as main transcriptc.547C>T p.Pro183Ser missense_variant 1/1 ENST00000498907.3 NP_004355.2 P49715-1
CEBPANM_001287424.2 linkuse as main transcriptc.652C>T p.Pro218Ser missense_variant 1/1 NP_001274353.1 P49715-4
CEBPANM_001287435.2 linkuse as main transcriptc.505C>T p.Pro169Ser missense_variant 1/1 NP_001274364.1 P49715-2
CEBPANM_001285829.2 linkuse as main transcriptc.190C>T p.Pro64Ser missense_variant 1/1 NP_001272758.1 P49715-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEBPAENST00000498907.3 linkuse as main transcriptc.547C>T p.Pro183Ser missense_variant 1/16 NM_004364.5 ENSP00000427514.1 P49715-1
ENSG00000267727ENST00000587312.1 linkuse as main transcriptn.410G>A non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.0000135
AC:
2
AN:
148118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000244
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:
0.0000151
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000425
AC:
5
AN:
1176062
Hom.:
0
Cov.:
33
AF XY:
0.00000694
AC XY:
4
AN XY:
576090
show subpopulations
Gnomad4 AFR exome
AF:
0.0000428
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000414
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000135
AC:
2
AN:
148118
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
72110
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000151
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

Acute myeloid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 08, 2023This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the CEBPA protein (p.Pro183Ser). 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: 565564). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
Benign
0.11
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
19
DANN
Benign
0.90
DEOGEN2
Benign
0.19
T
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.49
T
M_CAP
Pathogenic
0.47
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.86
N
REVEL
Benign
0.019
Sift
Benign
0.075
T
Sift4G
Benign
0.15
T
Polyphen
0.0010
B
Vest4
0.25
MutPred
0.24
Loss of catalytic residue at P183 (P = 0.005);
MVP
0.14
ClinPred
0.11
T
GERP RS
-0.82
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.077
gMVP
0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs998501847; hg19: chr19-33792774; API