chr19-33302224-ATGTCG-A

Variant names:

• chr19-33302224-ATGTCG-A
• rs1060502121
• NM_004364.5:c.186_190delCGACA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004364.5(CEBPA):​c.186_190delCGACA​(p.Asp63GlnfsTer43) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEBPA NM_004364.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.39

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 Likely_pathogenic. Variant got 8 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 0.827 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 19-33302224-ATGTCG-A is Pathogenic according to our data. Variant chr19-33302224-ATGTCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 408751.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.186_190delCGACA	p.Asp63GlnfsTer43	frameshift_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.291_295delCGACA	p.Asp98GlnfsTer43	frameshift_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.144_148delCGACA	p.Asp49GlnfsTer43	frameshift_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.-172_-168delCGACA		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.186_190delCGACA	p.Asp63GlnfsTer43	frameshift_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the production of the full length isoform (p42) of the CEBPA protein, which results in the preferential usage of an alternate downstream in-frame methionine at codon 120. Translation starting from this methionine results in a 30 kDa N-terminal truncated isoform of CEBPA that lacks the TAD1 domain, and has been shown to abrogate CEBPA function by acting as a dominant-negative allele (PMID: 11242107, 19953636, 26162409). While functional studies have not been performed to directly test the effect of this variant on CEBPA protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 408751). This premature translational stop signal has been observed in individual(s) with familial acute myeloid leukemia (Invitae). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Asp63Glnfs*43) in the CEBPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 296 amino acid(s) of the CEBPA protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502121; hg19: chr19-33793130;