chr19-33301848-GGGCGGCGGC-G

Variant names:

• chr19-33301848-GGGCGGCGGC-G
• rs746430067
• NM_004364.5:c.558_566delGCCGCCGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004364.5(CEBPA):​c.558_566delGCCGCCGCC​(p.Pro187_Pro189del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000146 in 1,310,710 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: CEBPA NM_004364.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.84

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:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 19-33301848-GGGCGGCGGC-G is Benign according to our data. Variant chr19-33301848-GGGCGGCGGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239924.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.558_566delGCCGCCGCC	p.Pro187_Pro189del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.663_671delGCCGCCGCC	p.Pro222_Pro224del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.516_524delGCCGCCGCC	p.Pro173_Pro175del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.201_209delGCCGCCGCC	p.Pro68_Pro70del	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.558_566delGCCGCCGCC	p.Pro187_Pro189del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.403_411delGGCGGCGGC		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 19 AN: 148062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000166

Gnomad OTH AF: 0.000490

GnomAD3 exomes AF: 0.000183 AC: 6 AN: 32872 Hom.: 0 AF XY: 0.000203 AC XY: 4 AN XY: 19706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000149 AC: 173 AN: 1162648 Hom.: 2 AF XY: 0.000157 AC XY: 89 AN XY: 568554

Gnomad4 AFR exome AF: 0.000217

Gnomad4 AMR exome AF: 0.000262

Gnomad4 ASJ exome AF: 0.0000588

Gnomad4 EAS exome AF: 0.0000833

Gnomad4 SAS exome AF: 0.000332

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000128 AC: 19 AN: 148062 Hom.: 0 Cov.: 32 AF XY: 0.0000693 AC XY: 5 AN XY: 72100

Gnomad4 AFR AF: 0.0000732

Gnomad4 AMR AF: 0.0000669

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000218

Gnomad4 NFE AF: 0.000166

Gnomad4 OTH AF: 0.000490

Bravo AF: 0.000117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Mar 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 3 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 a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 204396, 19304957, 21455213) -

CEBPA-related disorder Uncertain:1

May 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEBPA c.558_566del9 variant is predicted to result in an in-frame deletion (p.Pro187_Pro189del). This variant has been reported in individuals with acute myeloid leukemia (Ho et al. 2009. PubMed ID: 19304957; Supplemental Table 1, Green et al. 2010. PubMed ID: 20439648). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Acute myeloid leukemia Uncertain:1

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.558_566del, results in the deletion of 3 amino acid(s) of the CEBPA protein (p.Pro187_Pro189del), 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: 19304957, 20439648). ClinVar contains an entry for this variant (Variation ID: 239924). 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. -

Inborn genetic diseases Benign:1

Mar 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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: rs746430067; hg19: chr19-33792754;