rs1060502121

Positions:

• chr19-33302224-ATGTCG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004364.5(CEBPA):​c.186_190del​(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 (★). Synonymous variant affecting the same amino acid position (i.e. I62I) has been classified as Likely benign.

• 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 Pathogenic. Variant got 12 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 33 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/exons	MANE	UniProt
CEBPA	NM_004364.5	c.186_190del	p.Asp63GlnfsTer43	frameshift_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.291_295del	p.Asp98GlnfsTer43	frameshift_variant	1/1
CEBPA	NM_001287435.2	c.144_148del	p.Asp49GlnfsTer43	frameshift_variant	1/1
CEBPA	NM_001285829.2	c.-172_-168del		5_prime_UTR_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.186_190del	p.Asp63GlnfsTer43	frameshift_variant	1/1		NM_004364.5	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

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 variant is not present in population databases (gnomAD no frequency). 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;