chr19-33302163-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004364.5(CEBPA):ā€‹c.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

Scores

3
5
11

Clinical Significance

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

Conservation

PhyloP100: 4.25
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 -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
CEBPANM_004364.5 linkuse as main transcriptc.252C>G p.His84Gln missense_variant 1/1 ENST00000498907.3 NP_004355.2
CEBPANM_001287424.2 linkuse as main transcriptc.357C>G p.His119Gln missense_variant 1/1 NP_001274353.1
CEBPANM_001287435.2 linkuse as main transcriptc.210C>G p.His70Gln missense_variant 1/1 NP_001274364.1
CEBPANM_001285829.2 linkuse as main transcriptc.-106C>G 5_prime_UTR_variant 1/1 NP_001272758.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEBPAENST00000498907.3 linkuse as main transcriptc.252C>G p.His84Gln missense_variant 1/1 NM_004364.5 ENSP00000427514 P1P49715-1

Frequencies

GnomAD3 genomes
AF:
0.0000264
AC:
4
AN:
151382
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000174
AC:
23
AN:
1321438
Hom.:
0
Cov.:
33
AF XY:
0.0000199
AC XY:
13
AN XY:
651674
show subpopulations
Gnomad4 AFR exome
AF:
0.0000747
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:
0.0000173
Gnomad4 OTH exome
AF:
0.0000186
GnomAD4 genome
AF:
0.0000264
AC:
4
AN:
151382
Hom.:
0
Cov.:
32
AF XY:
0.0000406
AC XY:
3
AN XY:
73906
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.0000442
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

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 submitterclinical testingBaylor GeneticsAug 07, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 30, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2023This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.68
T
M_CAP
Pathogenic
0.92
D
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.091
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.23
T
Polyphen
0.97
D
Vest4
0.31
MutPred
0.23
Gain of solvent accessibility (P = 0.0374);
MVP
0.39
ClinPred
0.95
D
GERP RS
4.1
Varity_R
0.20
gMVP
0.44

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: rs878854700; hg19: chr19-33793069; COSMIC: COSV105881783; COSMIC: COSV105881783; API