rs538441046

chr19-33301854-C-Gchr19-33301854-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004364.5(CEBPA):c.561G>C(p.Pro187=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,277,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: CEBPA NM_004364.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.330

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-33301854-C-G is Benign according to our data. Variant chr19-33301854-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 415193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.561G>C	p.Pro187=	synonymous_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.666G>C	p.Pro222=	synonymous_variant	1/1
CEBPA	NM_001287435.2	c.519G>C	p.Pro173=	synonymous_variant	1/1
CEBPA	NM_001285829.2	c.204G>C	p.Pro68=	synonymous_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.561G>C	p.Pro187=	synonymous_variant	1/1		NM_004364.5	P1
	ENST00000587312.1	n.396C>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 53 AN: 146532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00445

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000364

Gnomad OTH AF: 0.000496

GnomAD3 exomes AF: 0.000698 AC: 30 AN: 42962 Hom.: 1 AF XY: 0.000818 AC XY: 21 AN XY: 25668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.000490

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.000768

GnomAD4 exome AF: 0.000344 AC: 389 AN: 1131268 Hom.: 1 Cov.: 32 AF XY: 0.000387 AC XY: 214 AN XY: 553426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.000887

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.0000412

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000368 AC: 54 AN: 146642 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 24 AN XY: 71406

Gnomad4 AFR AF: 0.0000491

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.000214

Gnomad4 SAS AF: 0.00445

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000379

Gnomad4 OTH AF: 0.000490

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2020

- -

CEBPA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 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). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 10, 2020

- -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	12
Dann	Benign	0.64

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: rs538441046; hg19: chr19-33792760;