19-33301848-GGGCGGCGGCGGC-GGGC

Position:

chr19-33301848-GGGCGGCGGCGGC-GGGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_004364.5(CEBPA):c.558_566del(p.Pro187_Pro189del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.84

Variant links:

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]

CEBPA links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein
CEBPA	NM_004364.5 linkuse as main transcript	c.558_566del	p.Pro187_Pro189del	inframe_deletion	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001285829.2 linkuse as main transcript	c.201_209del	p.Pro68_Pro70del	inframe_deletion	1/1		NP_001272758.1
CEBPA	NM_001287424.2 linkuse as main transcript	c.663_671del	p.Pro222_Pro224del	inframe_deletion	1/1		NP_001274353.1
CEBPA	NM_001287435.2 linkuse as main transcript	c.516_524del	p.Pro173_Pro175del	inframe_deletion	1/1		NP_001274364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3 linkuse as main transcript	c.558_566del	p.Pro187_Pro189del	inframe_deletion	1/1		NM_004364.5	ENSP00000427514	P1	P49715-1
	ENST00000587312.1 linkuse as main transcript	n.403_411del		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000128

AC:

AN:

148062

Hom.:

Cov.:

show subpopulations

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:

AN:

32872

Hom.:

AF XY:

0.000203

AC XY:

AN XY:

19706

show subpopulations

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.:

AF XY:

0.000157

AC XY:

AN XY:

568554

show subpopulations

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:

AN:

148062

Hom.:

Cov.:

AF XY:

0.0000693

AC XY:

AN XY:

72100

show subpopulations

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:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over