rs1433126196

Positions:

• chr19-33301781-G-A
• chr19-33301781-G-C

Variant summary

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

The NM_004364.5(CEBPA):​c.634C>T​(p.His212Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,065,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.634C>T	p.His212Tyr	missense_variant	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.739C>T	p.His247Tyr	missense_variant	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.592C>T	p.His198Tyr	missense_variant	1/1		NP_001274364.1
CEBPA	NM_001285829.2	c.277C>T	p.His93Tyr	missense_variant	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.634C>T	p.His212Tyr	missense_variant	1/1		NM_004364.5	ENSP00000427514	P1
	ENST00000587312.1	n.357-34G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1065648 Hom.: 0 Cov.: 22 AF XY: 0.00000391 AC XY: 2 AN XY: 512102

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: 0.00000220

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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 04, 2022

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 expected to disrupt CEBPA protein function. ClinVar contains an entry for this variant (Variation ID: 456696). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 212 of the CEBPA protein (p.His212Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.27
MutPred		0.29		Loss of sheet (P = 0.0357);
MVP		0.27
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.36

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: rs1433126196; hg19: chr19-33792687;