rs868242502

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_004364.5(CEBPA):c.261G>T(p.Gln87His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,408 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q87R) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.17

Publications

0 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 19-33302154-C-A is Benign according to our data. Variant chr19-33302154-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570045.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.261G>T	p.Gln87His	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.366G>T	p.Gln122His	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.219G>T	p.Gln73His	missense_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.-97G>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.261G>T	p.Gln87His	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1	P49715-1
CEBPA-DT	ENST00000718467.1 link	n.46+355C>A		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.*214C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151390

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

90320

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000156

AC:

AN:

1280018

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

629638

show subpopulations

African (AFR)

AF:

0.0000756

AC:

AN:

26454

American (AMR)

AF:

0.00

AC:

AN:

25038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21816

East Asian (EAS)

AF:

0.00

AC:

AN:

27442

South Asian (SAS)

AF:

0.00

AC:

AN:

63144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1014794

Other (OTH)

AF:

0.00

AC:

AN:

51632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151390

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73932

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41324

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67824

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:1

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 87 of the CEBPA protein (p.Gln87His). 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: 570045). 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. -

Inborn genetic diseases

Benign:1

Jan 13, 2025

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

Uncertain

0.36

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

PhyloP100

3.2

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Uncertain

0.010

Sift4G

Benign

0.13

Polyphen

0.99

Vest4

0.25

MutPred

0.24

Loss of helix (P = 0.1299);

MVP

0.54

ClinPred

0.86

GERP RS

4.1

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.28

gMVP

0.26

Mutation Taster

=71/29

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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rs868242502

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