rs752254340

Positions:

chr19-33302013-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_004364.5(CEBPA):c.402G>A(p.Ala134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,180,674 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

CEBPA
NM_004364.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.0350

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 19-33302013-C-T is Benign according to our data. Variant chr19-33302013-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239923.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}. Variant chr19-33302013-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.035 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00283 (420/148578) while in subpopulation NFE AF= 0.00429 (286/66658). AF 95% confidence interval is 0.00388. There are 1 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CEBPA	NM_004364.5 linkuse as main transcript	c.402G>A	p.Ala134=	synonymous_variant	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2 linkuse as main transcript	c.507G>A	p.Ala169=	synonymous_variant	1/1		NP_001274353.1
CEBPA	NM_001287435.2 linkuse as main transcript	c.360G>A	p.Ala120=	synonymous_variant	1/1		NP_001274364.1
CEBPA	NM_001285829.2 linkuse as main transcript	c.45G>A	p.Ala15=	synonymous_variant	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3 linkuse as main transcript	c.402G>A	p.Ala134=	synonymous_variant	1/1		NM_004364.5	ENSP00000427514	P1	P49715-1

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

420

AN:

148468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.0210

Gnomad AMR

AF:

0.00240

Gnomad ASJ

AF:

0.00411

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00572

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00147

GnomAD3 exomes

AF:

0.00187

AC:

AN:

2142

Hom.:

AF XY:

0.00176

AC XY:

AN XY:

1134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00235

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00266

AC:

2748

AN:

1032096

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1327

AN XY:

487920

show subpopulations

Gnomad4 AFR exome

AF:

0.000387

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00387

Gnomad4 EAS exome

AF:

0.0000933

Gnomad4 SAS exome

AF:

0.00170

Gnomad4 FIN exome

AF:

0.00560

Gnomad4 NFE exome

AF:

0.00275

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00283

AC:

420

AN:

148578

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

220

AN XY:

72452

show subpopulations

Gnomad4 AFR

AF:

0.000170

Gnomad4 AMR

AF:

0.00240

Gnomad4 ASJ

AF:

0.00411

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00572

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00145

Alfa

AF:

0.00688

Hom.:

Bravo

AF:

0.00214

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	This variant is associated with the following publications: (PMID: 25468431) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 31, 2018

- -

CEBPA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2020

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). -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 20, 2020

- -

Acute myeloid leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

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