19-33302231-T-G

Variant names:

• chr19-33302231-T-G
• NM_004364.5:c.184A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004364.5(CEBPA):​c.184A>C​(p.Ile62Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,344,108 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Decreased interaction with TRIB1. (size 0) in uniprot entity CEBPA_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.184A>C	p.Ile62Leu	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.289A>C	p.Ile97Leu	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.142A>C	p.Ile48Leu	missense_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.-174A>C		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.184A>C	p.Ile62Leu	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.44e-7 AC: 1 AN: 1344108 Hom.: 0 Cov.: 33 AF XY: 0.00000151 AC XY: 1 AN XY: 662872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.51e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.98	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		0.98	D
Vest4		0.51
MutPred		0.32		Gain of catalytic residue at I62 (P = 0.0519);
MVP		0.40
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.77
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-33793137;