19-33302343-G-T

Variant names:

• chr19-33302343-G-T
• rs1555742309
• NM_004364.5:c.72C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004364.5(CEBPA):​c.72C>A​(p.His24Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000835 in 1,198,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3614061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.72C>A	p.His24Gln	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.177C>A	p.His59Gln	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.30C>A	p.His10Gln	missense_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.-286C>A		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.72C>A	p.His24Gln	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
CEBPA-DT	ENST00000718467.1	n.46+544G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1198252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 583640

African (AFR) AF: 0.00 AC: 0 AN: 23572

American (AMR) AF: 0.00 AC: 0 AN: 9568

Ashkenazi Jewish (ASJ) AF: 0.0000639 AC: 1 AN: 15660

East Asian (EAS) AF: 0.00 AC: 0 AN: 27240

South Asian (SAS) AF: 0.00 AC: 0 AN: 45454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 983518

Other (OTH) AF: 0.00 AC: 0 AN: 48174

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

May 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the CEBPA protein (p.His24Gln). 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: 526816). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.070
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.055
Sift	Benign	0.093	T
Sift4G	Benign	0.25	T
Polyphen		0.65	P
Vest4		0.39
MutPred		0.16		Gain of solvent accessibility (P = 0.0081);
MVP		0.42
ClinPred		0.56	D
GERP RS		4.1
PromoterAI		0.13	Neutral
Varity_R		0.22
gMVP		0.43
Mutation Taster		=63/37	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

Other links and lift over

dbSNP: rs1555742309; hg19: chr19-33793249;