19-33302364-G-T

Position:

• chr19-33302364-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004364.5(CEBPA):​c.51C>A​(p.Ser17Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000912 in 1,315,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39336506).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.51C>A	p.Ser17Arg	missense_variant	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.156C>A	p.Ser52Arg	missense_variant	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.9C>A	p.Ser3Arg	missense_variant	1/1		NP_001274364.1
CEBPA	NM_001285829.2	c.-307C>A		5_prime_UTR_variant	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.51C>A	p.Ser17Arg	missense_variant	1/1	6	NM_004364.5	ENSP00000427514.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151424 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000945 AC: 11 AN: 1164040 Hom.: 0 Cov.: 32 AF XY: 0.0000107 AC XY: 6 AN XY: 562158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000934

Gnomad4 OTH exome AF: 0.0000428

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151424 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73934

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 17 of the CEBPA protein (p.Ser17Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEBPA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.072
Eigen_PC	Benign	0.029
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.57	T
Polyphen		0.99	D
Vest4		0.44
MutPred		0.21		Gain of solvent accessibility (P = 0.0055);
MVP		0.33
ClinPred		0.64	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.18
gMVP		0.47

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: rs1245499278; hg19: chr19-33793270;