19-33301868-G-T

Variant names:

• chr19-33301868-G-T
• rs998501847
• NM_004364.5:c.547C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_004364.5(CEBPA):​c.547C>A​(p.Pro183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,176,064 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P183S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.51
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17320421).
• BP6: Variant 19-33301868-G-T is Benign according to our data. Variant chr19-33301868-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 456691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.547C>A	p.Pro183Thr	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.652C>A	p.Pro218Thr	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.505C>A	p.Pro169Thr	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.547C>A	p.Pro183Thr	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.410G>T		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+69G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 51980 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000255 AC: 3 AN: 1176064 Hom.: 0 Cov.: 33 AF XY: 0.00000347 AC XY: 2 AN XY: 576092

African (AFR) AF: 0.00 AC: 0 AN: 23354

American (AMR) AF: 0.00 AC: 0 AN: 16978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17862

East Asian (EAS) AF: 0.00 AC: 0 AN: 24260

South Asian (SAS) AF: 0.00 AC: 0 AN: 50566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3184

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 966022

Other (OTH) AF: 0.00 AC: 0 AN: 46126

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Acute myeloid leukemia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.012
Sift	Benign	0.033	D
Sift4G	Uncertain	0.056	T
Polyphen		0.030	B
Vest4		0.27
MutPred		0.23		Gain of phosphorylation at P183 (P = 0.0073)
MVP		0.17
ClinPred		0.11	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.37
Mutation Taster		=85/15	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: rs998501847; hg19: chr19-33792774;