19-33302050-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004364.5(CEBPA):c.365G>A(p.Gly122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,203,880 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G122R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.03

Publications

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

BP4

Computational evidence support a benign effect (MetaRNN=0.14498684).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.365G>A	p.Gly122Glu	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.470G>A	p.Gly157Glu	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.323G>A	p.Gly108Glu	missense_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.8G>A	p.Gly3Glu	missense_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.365G>A	p.Gly122Glu	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1	P49715-1
CEBPA-DT	ENST00000718467.1 link	n.46+251C>T		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.*110C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

148660

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:

0.000800

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

AF:

0.00000474

AC:

AN:

1055220

Hom.:

Cov.:

AF XY:

0.00000400

AC XY:

AN XY:

499986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21210

American (AMR)

AF:

0.00

AC:

AN:

6990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12314

East Asian (EAS)

AF:

0.000176

AC:

AN:

22700

South Asian (SAS)

AF:

0.00

AC:

AN:

20264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

899742

Other (OTH)

AF:

0.0000246

AC:

AN:

40622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000269

AC:

AN:

148660

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

72464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40946

American (AMR)

AF:

0.00

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.000800

AC:

AN:

4998

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66902

Other (OTH)

AF:

0.00

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:3

Mar 11, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 122 of the CEBPA protein (p.Gly122Glu). This variant is present in population databases (no rsID available, gnomAD 0.1%). 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: 456682). 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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jul 26, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15756005, 25468431) -

Inborn genetic diseases

Benign:1

Dec 12, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.0

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.43

REVEL

Benign

0.033

Sift

Benign

0.098

Sift4G

Benign

0.32

Polyphen

0.60

Vest4

0.21

MutPred

0.27

Gain of solvent accessibility (P = 0.024);

MVP

0.21

ClinPred

0.20

GERP RS

2.5

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.068

gMVP

0.15

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over