19-33301706-G-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.709C>A(p.Pro237Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,152,732 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. P237L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.99

Publications

2 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:

ENSG00000267727 (HGNC:):

ENSG00000267727 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10686156).

BS2

High AC in GnomAd4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	NM_004364.5	MANE Select	c.709C>A	p.Pro237Thr	missense	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.814C>A	p.Pro272Thr	missense	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.667C>A	p.Pro223Thr	missense	Exon 1 of 1	NP_001274364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.709C>A	p.Pro237Thr	missense	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.356+72G>T		intron	N/A
CEBPA-DT	ENST00000718467.1		n.-48G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

148434

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000439

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

AF:

0.0000119

AC:

AN:

1004298

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

475426

show subpopulations

African (AFR)

AF:

0.000550

AC:

AN:

20006

American (AMR)

AF:

0.000175

AC:

AN:

5722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10436

East Asian (EAS)

AF:

0.00

AC:

AN:

17450

South Asian (SAS)

AF:

0.00

AC:

AN:

19080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

874022

Other (OTH)

AF:

0.00

AC:

AN:

37770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.000121

AC:

AN:

148434

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

72326

show subpopulations

African (AFR)

AF:

0.000439

AC:

AN:

41042

American (AMR)

AF:

0.00

AC:

AN:

14960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66654

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:3

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 06, 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 threonine, which is neutral and polar, at codon 237 of the CEBPA protein (p.Pro237Thr). This variant is present in population databases (no rsID available, gnomAD 0.04%). 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: 526800). 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.

Sep 26, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Feb 16, 2024

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; Has not been previously published as pathogenic or benign to our knowledge

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 11, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Inborn genetic diseases

Benign:1

Nov 24, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.23

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

PhyloP100

4.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.3

REVEL

Benign

0.057

Sift

Benign

0.66

Sift4G

Benign

0.60

Polyphen

0.14

Vest4

0.12

MutPred

0.12

Gain of phosphorylation at P237 (P = 0.0269)

MVP

0.37

ClinPred

0.091

GERP RS

1.9

Varity_R

0.058

gMVP

0.36

Mutation Taster

=76/24

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over