19-33301825-GGCGGGTGCGGGT-GGCGGGT

Position:

• chr19-33301825-GGCGGGTGCGGGT-GGCGGGT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004364.5(CEBPA):​c.584_589del​(p.His195_Pro196del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,263,420 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: CEBPA NM_004364.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 3.20

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.584_589del	p.His195_Pro196del	inframe_deletion	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001285829.2	c.227_232del	p.His76_Pro77del	inframe_deletion	1/1		NP_001272758.1
CEBPA	NM_001287424.2	c.689_694del	p.His230_Pro231del	inframe_deletion	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.542_547del	p.His181_Pro182del	inframe_deletion	1/1		NP_001274364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.584_589del	p.His195_Pro196del	inframe_deletion	1/1		NM_004364.5	ENSP00000427514	P1
	ENST00000587312.1	n.383_388del		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 25 AN: 148158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000195

Gnomad OTH AF: 0.000491

GnomAD3 exomes AF: 0.000196 AC: 2 AN: 10180 Hom.: 0 AF XY: 0.000309 AC XY: 2 AN XY: 6468

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000760

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000291 AC: 324 AN: 1115154 Hom.: 1 AF XY: 0.000292 AC XY: 158 AN XY: 541312

Gnomad4 AFR exome AF: 0.000409

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000548

Gnomad4 FIN exome AF: 0.000251

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.0000916

GnomAD4 genome AF: 0.000169 AC: 25 AN: 148266 Hom.: 0 Cov.: 31 AF XY: 0.000152 AC XY: 11 AN XY: 72288

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.0000668

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000109

Gnomad4 NFE AF: 0.000195

Gnomad4 OTH AF: 0.000485

Bravo AF: 0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2022	In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34587721, 21455213) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 14, 2022

DNA sequence analysis of the CEBPA demonstrated a six base pair deletion in exon 1, c.584_589del. This in-frame deletion is predicted to result in the deletion of two amino acid residues, p.His195_Pro196del. This deletion does not appear to have been previously described in individuals with CEBPA -related disorders. This deletion has not been described in population databases such as ExAC and gnomAD; however the allele frequency estimates may not be reliable in gnomAD (dbSNP rs1002805239). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined. -

CEBPA-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2023

The CEBPA c.584_589del6 variant is predicted to result in an in-frame deletion (p.His195_Pro196del). This variant has been reported as a germline variant in an individual with acute myeloid leukemia (Szankasi. 2010. PubMed ID: 20970189). This variant is reported in 0.034% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-33792731-GGCGGGT-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Sep 15, 2021

- -

Acute myeloid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2023

This variant, c.584_589del, results in the deletion of 2 amino acid(s) of the CEBPA protein (p.His195_Pro196del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with acute myeloid leukemia (PMID: 20970189). ClinVar contains an entry for this variant (Variation ID: 408757). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs762459325; hg19: chr19-33792731;