19-33301848-GGGCGGCGGCGGC-GGGCGGCGGC

Position:

chr19-33301848-GGGCGGCGGCGGC-GGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004364.5(CEBPA):c.564_566del(p.Pro189del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,289,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.21

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 Benign. Variant got -9 ACMG points.

BP6

Variant 19-33301848-GGGC-G is Benign according to our data. Variant chr19-33301848-GGGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 641289.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00203 (2322/1141150) while in subpopulation AMR AF= 0.00846 (124/14660). AF 95% confidence interval is 0.00776. There are 0 homozygotes in gnomad4_exome. There are 1289 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 2322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CEBPA	NM_004364.5 linkuse as main transcript	c.564_566del	p.Pro189del	inframe_deletion	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001285829.2 linkuse as main transcript	c.207_209del	p.Pro70del	inframe_deletion	1/1		NP_001272758.1
CEBPA	NM_001287424.2 linkuse as main transcript	c.669_671del	p.Pro224del	inframe_deletion	1/1		NP_001274353.1
CEBPA	NM_001287435.2 linkuse as main transcript	c.522_524del	p.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.564_566del	p.Pro189del	inframe_deletion	1/1		NM_004364.5	ENSP00000427514	P1	P49715-1
	ENST00000587312.1 linkuse as main transcript	n.409_411del		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

148056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00203

AC:

2322

AN:

1141150

Hom.:

AF XY:

0.00231

AC XY:

1289

AN XY:

557336

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.00846

Gnomad4 ASJ exome

AF:

0.00424

Gnomad4 EAS exome

AF:

0.00204

Gnomad4 SAS exome

AF:

0.00845

Gnomad4 FIN exome

AF:

0.00517

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.00279

GnomAD4 genome

AF:

0.0000270

AC:

AN:

148056

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

72096

show subpopulations

Gnomad4 AFR

AF:

0.0000488

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.00135

AC:

AN:

2988

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Aug 18, 2021

- -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2019

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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with CEBPA-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.564_566delGCC, results in the deletion of 1 amino acid(s) of the CEBPA protein (p.Pro189del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

This alteration is classified as 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 09, 2021

- -

CEBPA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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