NM_004364.5:c.37C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004364.5(CEBPA):c.37C>G(p.Pro13Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,440 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. P13T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 links:

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

CEBPA-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.37C>G	p.Pro13Ala	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.142C>G	p.Pro48Ala	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.-6C>G		5_prime_UTR_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.-321C>G		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
CEBPA	ENST00000498907.3 link	c.37C>G	p.Pro13Ala	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1		P49715-1
CEBPA-DT	ENST00000718467.1 link	n.46+579G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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

Cov.:

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151440

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73980

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67804

Other (OTH)

AF:

0.00

AC:

AN:

2080

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

Age Distribution

Genome Het

Variant carriers

<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.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:1

Sep 15, 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 526818). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 13 of the CEBPA protein (p.Pro13Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

PhyloP100

6.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.2

REVEL

Benign

0.17

Sift

Benign

0.075

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.24

MutPred

0.22

Loss of catalytic residue at P13 (P = 0.0055);

MVP

0.54

ClinPred

0.95

GERP RS

4.1

PromoterAI

-0.0015

Neutral

(source)

Varity_R

0.19

gMVP

0.42

Mutation Taster

=55/45

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over