19-33302171-A-G

Variant names:

• chr19-33302171-A-G
• rs2145263519
• NM_004364.5:c.244T>C
• CEBPA p.Phe82Leu

Variant summary

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

The NM_004364.5(CEBPA):​c.244T>C​(p.Phe82Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F82S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.73
• Publications: 0 publications found

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

ENSG00000267727 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.244T>C	p.Phe82Leu	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.349T>C	p.Phe117Leu	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.202T>C	p.Phe68Leu	missense	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.244T>C	p.Phe82Leu	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+372A>G		intron	N/A
	ENSG00000267727	ENST00000587312.1	TSL:3	n.*231A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1325434 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 653708

African (AFR) AF: 0.00 AC: 0 AN: 26836

American (AMR) AF: 0.00 AC: 0 AN: 27836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22904

East Asian (EAS) AF: 0.00 AC: 0 AN: 28446

South Asian (SAS) AF: 0.00 AC: 0 AN: 71816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041290

Other (OTH) AF: 0.00 AC: 0 AN: 54192

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.7
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.021	Neutral
Varity_R		0.51
gMVP		0.41
Mutation Taster		=65/35	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2145263519;

hg19: chr19-33793077;