rs1311096326

chr19-33302050-C-Gchr19-33302050-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004364.5(CEBPA):c.365G>C(p.Gly122Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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. G122E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.03

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11317372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.365G>C	p.Gly122Ala	missense_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.470G>C	p.Gly157Ala	missense_variant	1/1
CEBPA	NM_001287435.2	c.323G>C	p.Gly108Ala	missense_variant	1/1
CEBPA	NM_001285829.2	c.8G>C	p.Gly3Ala	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.365G>C	p.Gly122Ala	missense_variant	1/1		NM_004364.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 22, 2021

- -

Acute myeloid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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. ClinVar contains an entry for this variant (Variation ID: 1692811). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 122 of the CEBPA protein (p.Gly122Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.018
Sift	Benign	0.50	T
Sift4G	Benign	0.42	T
Polyphen		0.38	B
Vest4		0.11
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.11
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.045
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-33792956;