19-33302091-G-C

Variant names:

• chr19-33302091-G-C
• rs1555742221
• NM_004364.5:c.324C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004364.5(CEBPA):​c.324C>G​(p.Tyr108*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y108Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEBPA NM_004364.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.869
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-33302091-G-C is Pathogenic according to our data. Variant chr19-33302091-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 938430.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.324C>G	p.Tyr108*	stop_gained	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.429C>G	p.Tyr143*	stop_gained	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.282C>G	p.Tyr94*	stop_gained	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.324C>G	p.Tyr108*	stop_gained	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+292G>C		intron	N/A
	ENSG00000267727	ENST00000587312.1	TSL:3	n.*151G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.60e-7 AC: 1 AN: 1162420 Hom.: 0 Cov.: 33 AF XY: 0.00000178 AC XY: 1 AN XY: 562604

African (AFR) AF: 0.00 AC: 0 AN: 23630

American (AMR) AF: 0.00 AC: 0 AN: 13484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17628

East Asian (EAS) AF: 0.00 AC: 0 AN: 25878

South Asian (SAS) AF: 0.00 AC: 0 AN: 38122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3230

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 956122

Other (OTH) AF: 0.00 AC: 0 AN: 45924

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Acute myeloid leukemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		0.87
Vest4		0.63
GERP RS		2.7
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1555742221; hg19: chr19-33792997; COSMIC: COSV57198636;