Genetic Variant CEBPA:p.Ile341Leu (chr19-33301394-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000498907.3(CEBPA):c.1021A>C(p.Ile341Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I341V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CEBPA
ENST00000498907.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.19

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 Gene-Disease associations (from GenCC):

acute myeloid leukemia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

CEBPA links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in ENST00000498907.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16747242).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000498907.3. 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.1021A>C	p.Ile341Leu	missense	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.1126A>C	p.Ile376Leu	missense	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.979A>C	p.Ile327Leu	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.1021A>C	p.Ile341Leu	missense	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.116T>G		non_coding_transcript_exon	Exon 1 of 2
ENSG00000267580	ENST00000589932.1	TSL:2	n.*226T>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.20

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.049

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.27

PhyloP100

2.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.44

REVEL

Benign

0.16

Sift

Benign

0.79

Sift4G

Benign

0.92

Polyphen

0.68

Vest4

0.33

MutPred

0.46

Gain of disorder (P = 0.021)

MVP

0.24

ClinPred

0.59

GERP RS

4.7

Varity_R

0.28

gMVP

0.70

Mutation Taster

=49/51

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over