rs571969199

Positions:

• chr19-33301659-C-A
• chr19-33301659-C-G
• chr19-33301659-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004364.5(CEBPA):​c.756G>T​(p.Ala252=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,488,680 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (12 hom.)
• Consequence: CEBPA NM_004364.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0550

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 19-33301659-C-A is Benign according to our data. Variant chr19-33301659-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 415189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33301659-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.055 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00708 (1061/149830) while in subpopulation AFR AF= 0.0245 (1011/41270). AF 95% confidence interval is 0.0232. There are 14 homozygotes in gnomad4. There are 504 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1061 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.756G>T	p.Ala252=	synonymous_variant	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.861G>T	p.Ala287=	synonymous_variant	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.714G>T	p.Ala238=	synonymous_variant	1/1		NP_001274364.1
CEBPA	NM_001285829.2	c.399G>T	p.Ala133=	synonymous_variant	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.756G>T	p.Ala252=	synonymous_variant	1/1		NM_004364.5	ENSP00000427514	P1
	ENST00000587312.1	n.356+25C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1058 AN: 149722 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00193

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00389

GnomAD3 exomes AF: 0.00183 AC: 176 AN: 96236 Hom.: 3 AF XY: 0.00150 AC XY: 81 AN XY: 54102

Gnomad AFR exome AF: 0.0600

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000830 AC: 1111 AN: 1338850 Hom.: 12 Cov.: 31 AF XY: 0.000756 AC XY: 499 AN XY: 659876

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000967

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00708 AC: 1061 AN: 149830 Hom.: 14 Cov.: 32 AF XY: 0.00689 AC XY: 504 AN XY: 73142

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00193

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000149

Gnomad4 OTH AF: 0.00385

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00774

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2018

- -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.8
DANN	Benign	0.89

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: rs571969199; hg19: chr19-33792565; COSMIC: COSV105200112; COSMIC: COSV105200112;