rs1555742209

Variant names:

• chr19-33302057-T-C
• rs1555742209
• NM_004364.5:c.358A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-33302057-T-C
• chr19-33302057-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001285829.2(CEBPA):​c.1A>G​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEBPA NM_001285829.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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]

ENSG00000267727 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 99 codons. Genomic position: 33301763. Lost 0.410 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.358A>G	p.Met120Val	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001285829.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 1		NP_001272758.1
CEBPA	NM_001287424.2	c.463A>G	p.Met155Val	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.316A>G	p.Met106Val	missense_variant	Exon 1 of 1		NP_001274364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.358A>G	p.Met120Val	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.*117T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 120 of the CEBPA protein (p.Met120Val). 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. 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: 456681). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.029
Sift	Benign	0.48	T
Sift4G	Benign	0.51	T
Polyphen		0.028	B
Vest4		0.26
MutPred		0.25		Gain of sheet (P = 0.0344);
MVP		0.10
ClinPred		0.064	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.27

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: rs1555742209; hg19: chr19-33792963;