19-33301825-GGCGGGTGCGGGT-GGCGGGT

Variant names:

• chr19-33301825-GGCGGGT-G
• rs762459325
• NM_004364.5:c.584_589delACCCGC

Variant summary

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

The NM_004364.5(CEBPA):​c.584_589delACCCGC​(p.His195_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 0.000276 in 1,263,420 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H195H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: CEBPA NM_004364.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• 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 GnomAd4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.584_589delACCCGC	p.His195_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.689_694delACCCGC	p.His230_Pro231del	disruptive_inframe_deletion	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.542_547delACCCGC	p.His181_Pro182del	disruptive_inframe_deletion	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.584_589delACCCGC	p.His195_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.383_388delGGTGCG		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+42_46+47delGGTGCG		intron	N/A

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

GnomAD2 exomes AF: 0.000196 AC: 2 AN: 10180 AF XY: 0.000309

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 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

African (AFR) AF: 0.000409 AC: 9 AN: 21998

American (AMR) AF: 0.000113 AC: 1 AN: 8816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13896

East Asian (EAS) AF: 0.00 AC: 0 AN: 23680

South Asian (SAS) AF: 0.000548 AC: 20 AN: 36528

European-Finnish (FIN) AF: 0.000251 AC: 6 AN: 23926

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

European-Non Finnish (NFE) AF: 0.000302 AC: 284 AN: 939774

Other (OTH) AF: 0.0000916 AC: 4 AN: 43660

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

African (AFR) AF: 0.000146 AC: 6 AN: 41082

American (AMR) AF: 0.0000668 AC: 1 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4978

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000195 AC: 13 AN: 66552

Other (OTH) AF: 0.000485 AC: 1 AN: 2060

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.000181

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Acute myeloid leukemia (1)
-	1	-	CEBPA-related disorder (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=149/51	polymorphism

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: COSV104411195;