chr19-33301036-G-A

Position:

• chr19-33301036-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004364.5(CEBPA):​c.*302C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 502,302 control chromosomes in the GnomAD database, including 520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (106 hom., cov: 32)
  • Exomes 𝑓: 0.018 (414 hom.)
• Consequence: CEBPA NM_004364.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-33301036-G-A is Benign according to our data. Variant chr19-33301036-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1187270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.*302C>T		3_prime_UTR_variant	1/1	ENST00000498907.3
CEBPA	NM_001285829.2	c.*302C>T		3_prime_UTR_variant	1/1
CEBPA	NM_001287424.2	c.*302C>T		3_prime_UTR_variant	1/1
CEBPA	NM_001287435.2	c.*302C>T		3_prime_UTR_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.*302C>T		3_prime_UTR_variant	1/1		NM_004364.5	P1
	ENST00000589932.1	n.542-15G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1400 AN: 152194 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0614

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.0176 AC: 6173 AN: 349990 Hom.: 414 Cov.: 3 AF XY: 0.0184 AC XY: 3329 AN XY: 180440

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.00404

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.0494

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000338

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.00923 AC: 1406 AN: 152312 Hom.: 106 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74476

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.0602

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00276 Hom.: 8

Bravo AF: 0.00893

Asia WGS AF: 0.147 AC: 508 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4142943; hg19: chr19-33791942;