19-33302091-G-C

Position:

• chr19-33302091-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong 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 (★★).

• 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

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 Pathogenic. Variant got 14 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. Fraction of 0.699 CDS is truncated, and there are 0 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 [Likely_pathogenic]. Clinvar id is 938430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.324C>G	p.Tyr108*	stop_gained	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.429C>G	p.Tyr143*	stop_gained	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.282C>G	p.Tyr94*	stop_gained	1/1		NP_001274364.1
CEBPA	NM_001285829.2	c.-34C>G		5_prime_UTR_variant	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.324C>G	p.Tyr108*	stop_gained	1/1	6	NM_004364.5	ENSP00000427514.1

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

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: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 12, 2022	The CEPBA c.324C>G (p.Tyr108Ter) change is a nonsense variant located in the CEBPA region encoding the N-terminal C/EBPα protein, which is predicted to produce a truncated protein (PVS1_strong; PMID: 30192042). This variant is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant has been identified in an individual with acute myeloid leukemia in which the tumor harbored a second somatic mutation affecting the C-terminus (PP4; internal data), a characteristic feature of germline CEBPA-associated acute myeloid leukemia (PMID: 26162409). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CEBPA protein. Other variant(s) that disrupt this region (p.Glu148*) have been determined to be pathogenic (PMID: 29296967). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with CEBPA-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the CEBPA gene (p.Tyr108*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 251 amino acids of the CEBPA protein. -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.63
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

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