rs1348778034

chr19-33302321-C-Achr19-33302321-C-Gchr19-33302321-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004364.5(CEBPA):c.94G>T(p.Gly32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 in 1,245,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G32S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.944

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30144286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.94G>T	p.Gly32Cys	missense_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.199G>T	p.Gly67Cys	missense_variant	1/1
CEBPA	NM_001287435.2	c.52G>T	p.Gly18Cys	missense_variant	1/1
CEBPA	NM_001285829.2	c.-264G>T		5_prime_UTR_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.94G>T	p.Gly32Cys	missense_variant	1/1		NM_004364.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000219 AC: 1 AN: 45764 Hom.: 0 AF XY: 0.0000376 AC XY: 1 AN XY: 26618

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: 0.0000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.03e-7 AC: 1 AN: 1245064 Hom.: 0 Cov.: 33 AF XY: 0.00000164 AC XY: 1 AN XY: 610824

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: 9.95e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.59	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.59	P
Vest4		0.28
MutPred		0.22		Loss of methylation at R35 (P = 0.0806);
MVP		0.39
ClinPred		0.25	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.38

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: rs1348778034; hg19: chr19-33793227;