rs12691

Variant names:

• chr19-33300221-G-A
• rs12691
• NM_004364.5:c.*1117C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004364.5(CEBPA):​c.*1117C>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 0.146 in 233,458 control chromosomes in the GnomAD database, including 3,048 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2277 hom., cov: 32)
  • Exomes 𝑓: 0.13 (771 hom.)
• Consequence: CEBPA NM_004364.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• acute myeloid leukemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000267580 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.*1117C>T		3_prime_UTR_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.*1117C>T		3_prime_UTR_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.*1117C>T		3_prime_UTR_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.*1117C>T		3_prime_UTR_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.*1117C>T		3_prime_UTR_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267580	ENST00000589932.1	n.288G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23875 AN: 151996 Hom.: 2264 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.155

GnomAD4 exome AF: 0.126 AC: 10226 AN: 81344 Hom.: 771 Cov.: 0 AF XY: 0.125 AC XY: 4688 AN XY: 37434

African (AFR) AF: 0.257 AC: 1001 AN: 3900

American (AMR) AF: 0.102 AC: 254 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 648 AN: 5124

East Asian (EAS) AF: 0.0151 AC: 173 AN: 11448

South Asian (SAS) AF: 0.0997 AC: 70 AN: 702

European-Finnish (FIN) AF: 0.0916 AC: 35 AN: 382

Middle Eastern (MID) AF: 0.181 AC: 89 AN: 492

European-Non Finnish (NFE) AF: 0.141 AC: 7034 AN: 50026

Other (OTH) AF: 0.136 AC: 922 AN: 6772

GnomAD4 genome AF: 0.157 AC: 23918 AN: 152114 Hom.: 2277 Cov.: 32 AF XY: 0.153 AC XY: 11371 AN XY: 74344

African (AFR) AF: 0.254 AC: 10536 AN: 41474

American (AMR) AF: 0.117 AC: 1783 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3472

East Asian (EAS) AF: 0.00988 AC: 51 AN: 5164

South Asian (SAS) AF: 0.0834 AC: 402 AN: 4818

European-Finnish (FIN) AF: 0.0954 AC: 1010 AN: 10588

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9220 AN: 67990

Other (OTH) AF: 0.152 AC: 321 AN: 2112

Alfa AF: 0.144 Hom.: 1755

Bravo AF: 0.163

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12691; hg19: chr19-33791127;