rs192240793

chr19-33301842-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004364.5(CEBPA):c.573C>T(p.His191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,311,920 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (112 hom., cov: 32)
  • Exomes 𝑓: 0.017 (299 hom.)
• Consequence: CEBPA NM_004364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.839

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-33301842-G-A is Benign according to our data. Variant chr19-33301842-G-A is described in ClinVar as [Benign]. Clinvar id is 259294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33301842-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.839 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.573C>T	p.His191=	synonymous_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.678C>T	p.His226=	synonymous_variant	1/1
CEBPA	NM_001287435.2	c.531C>T	p.His177=	synonymous_variant	1/1
CEBPA	NM_001285829.2	c.216C>T	p.His72=	synonymous_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.573C>T	p.His191=	synonymous_variant	1/1		NM_004364.5	P1
	ENST00000587312.1	n.384G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 2968 AN: 148384 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.00416

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.0274

GnomAD3 exomes AF: 0.0339 AC: 1245 AN: 36722 Hom.: 63 AF XY: 0.0264 AC XY: 576 AN XY: 21838

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00605

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0171 AC: 19871 AN: 1163428 Hom.: 299 Cov.: 31 AF XY: 0.0165 AC XY: 9378 AN XY: 568472

Gnomad4 AFR exome AF: 0.00268

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0000411

Gnomad4 SAS exome AF: 0.00621

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0200 AC: 2971 AN: 148492 Hom.: 112 Cov.: 32 AF XY: 0.0216 AC XY: 1560 AN XY: 72374

Gnomad4 AFR AF: 0.00415

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0275

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.0271

Alfa AF: 0.0156 Hom.: 6

Bravo AF: 0.0252

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2018	- -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	11
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs192240793; hg19: chr19-33792748; COSMIC: COSV57200682; COSMIC: COSV57200682;