rs762459325

Variant names:

• chr19-33301825-GGCGGGTGCGGGT-G
• rs762459325
• NM_004364.5:c.578_589delACCCGCACCCGC

Your query was ambiguous. Multiple possible variants found:

• chr19-33301825-GGCGGGTGCGGGT-G
• chr19-33301825-GGCGGGTGCGGGT-GGCGGGT
• chr19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGT
• chr19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGTGCGGGT
• chr19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGTGCGGGTGCGGGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_004364.5(CEBPA):​c.578_589delACCCGCACCCGC​(p.His193_Pro196del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 1,115,488 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H193H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CEBPA NM_004364.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.20
• Publications: 22 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]

ENSG00000267727 (HGNC:):

CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004364.5
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.578_589delACCCGCACCCGC	p.His193_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.683_694delACCCGCACCCGC	p.His228_Pro231del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.536_547delACCCGCACCCGC	p.His179_Pro182del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.221_232delACCCGCACCCGC	p.His74_Pro77del	disruptive_inframe_deletion	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.578_589delACCCGCACCCGC	p.His193_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.377_388delGGTGCGGGTGCG		non_coding_transcript_exon_variant	Exon 2 of 2	3
CEBPA-DT	ENST00000718467.1	n.46+36_46+47delGGTGCGGGTGCG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000896 AC: 10 AN: 1115488 Hom.: 0 AF XY: 0.0000111 AC XY: 6 AN XY: 541524

African (AFR) AF: 0.00 AC: 0 AN: 21998

American (AMR) AF: 0.00 AC: 0 AN: 8826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13910

East Asian (EAS) AF: 0.00 AC: 0 AN: 23690

South Asian (SAS) AF: 0.00 AC: 0 AN: 36604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2876

European-Non Finnish (NFE) AF: 0.0000106 AC: 10 AN: 939968

Other (OTH) AF: 0.00 AC: 0 AN: 43670

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578_589del12 variant (also known as p.H193_P196del) is located in coding exon 1 of the CEBPA gene. This variant results from an in-frame deletion of 12 nucleotides (ACCCGCACCCGC) at positions 578 to 589. This results in the in-frame deletion of 4 amino acids (HPHP) at codons 193 to 196. These amino acid positions are conserved on limited sequence alignment. Based on the available evidence, the clinical significance of this variant remains unclear. -

Acute myeloid leukemia Uncertain:1

Nov 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.578_589del, results in the deletion of 4 amino acid(s) of the CEBPA protein (p.His193_Pro196del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 526815). 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

Splicing

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

Other links and lift over

dbSNP: rs762459325; hg19: chr19-33792731; COSMIC: COSV57199477;