rs780335632

chr19-33301612-C-Achr19-33301612-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_004364.5(CEBPA):c.803G>T(p.Gly268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,443,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G268C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.05

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest Interaction with FOXO1 (size 114) in uniprot entity CEBPA_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_004364.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.17091593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.803G>T	p.Gly268Val	missense_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.908G>T	p.Gly303Val	missense_variant	1/1
CEBPA	NM_001287435.2	c.761G>T	p.Gly254Val	missense_variant	1/1
CEBPA	NM_001285829.2	c.446G>T	p.Gly149Val	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.803G>T	p.Gly268Val	missense_variant	1/1		NM_004364.5	P1
	ENST00000587312.1	n.334C>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000141 AC: 3 AN: 213054 Hom.: 0 AF XY: 0.00000848 AC XY: 1 AN XY: 117856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000320

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1443362 Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9 AN XY: 717342

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: 0.0000172

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000853 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2023	ClinVar contains an entry for this variant (Variation ID: 526807). 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. 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. This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. This variant is present in population databases (rs780335632, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 268 of the CEBPA protein (p.Gly268Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	15
Dann	Benign	0.91
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.027
Sift	Benign	0.087	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0676);
MVP		0.18
ClinPred		0.29	T
GERP RS		-0.79
Varity_R		0.18
gMVP		0.51

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: rs780335632; hg19: chr19-33792518;