rs1027991203

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004364.5(CEBPA):c.325C>T(p.Pro109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,310,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. P109A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.11

Publications

3 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 links:

CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

CEBPA-DT links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18087432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.325C>T	p.Pro109Ser	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.430C>T	p.Pro144Ser	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.-33C>T		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1	P49715-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEBPA	ENST00000498907.3 link	c.325C>T	p.Pro109Ser	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1	P49715-1
CEBPA-DT	ENST00000718467.1 link	n.46+291G>A		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.*150G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000199

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:

0.0000412

AC:

AN:

48592

AF XY:

0.0000349

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:

0.000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1160284

Hom.:

Cov.:

AF XY:

0.00000534

AC XY:

AN XY:

561344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23598

American (AMR)

AF:

0.00

AC:

AN:

13392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17478

East Asian (EAS)

AF:

0.00

AC:

AN:

25828

South Asian (SAS)

AF:

0.00

AC:

AN:

37650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3208

European-Non Finnish (NFE)

AF:

0.00000419

AC:

AN:

955038

Other (OTH)

AF:

0.00

AC:

AN:

45828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149810

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41218

American (AMR)

AF:

0.00

AC:

AN:

15098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000200

AC:

AN:

5008

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67256

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:2

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 109 of the CEBPA protein (p.Pro109Ser). 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: 408750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Aug 29, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P109S variant (also known as c.325C>T), located in coding exon 1 of the CEBPA gene, results from a C to T substitution at nucleotide position 325. The proline at codon 109 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.46

REVEL

Benign

0.017

Sift

Benign

0.068

Sift4G

Benign

0.39

Polyphen

0.0010

Vest4

0.13

MutPred

0.21

Gain of glycosylation at P109 (P = 0.0065);

MVP

0.26

ClinPred

0.049

GERP RS

3.0

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.084

gMVP

0.31

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over