rs1049967

Variant names:

• chr19-33301661-C-A
• rs1049967
• NM_004364.5:c.754G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004364.5(CEBPA):​c.754G>T​(p.Ala252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000405 in 1,480,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A252A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.704
• Publications: 4 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]

ENSG00000267727 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.072671354).

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.754G>T	p.Ala252Ser	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.859G>T	p.Ala287Ser	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.712G>T	p.Ala238Ser	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.754G>T	p.Ala252Ser	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.356+27C>A		intron	N/A
	CEBPA-DT	ENST00000718467.1		n.-93C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149596 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000298

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000301 AC: 4 AN: 1330930 Hom.: 0 Cov.: 31 AF XY: 0.00000153 AC XY: 1 AN XY: 655564

African (AFR) AF: 0.00 AC: 0 AN: 27584

American (AMR) AF: 0.00 AC: 0 AN: 29878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22454

East Asian (EAS) AF: 0.00 AC: 0 AN: 31204

South Asian (SAS) AF: 0.00 AC: 0 AN: 72716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1050904

Other (OTH) AF: 0.00 AC: 0 AN: 55088

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149596 Hom.: 0 Cov.: 32 AF XY: 0.0000274 AC XY: 2 AN XY: 72970

African (AFR) AF: 0.00 AC: 0 AN: 41140

American (AMR) AF: 0.00 AC: 0 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67208

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.8
DANN	Benign	0.91
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.70
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.036
Sift	Benign	0.82	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.16		Gain of glycosylation at A252 (P = 0.0071)
MVP		0.085
ClinPred		0.031	T
GERP RS		-1.6
Varity_R		0.042
gMVP		0.40
Mutation Taster		=90/10	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: rs1049967; hg19: chr19-33792567;