19-33301761-C-T

Variant names:

• chr19-33301761-C-T
• rs1555742071
• NM_004364.5:c.654G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004364.5(CEBPA):​c.654G>A​(p.Met218Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000587 in 1,191,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M218V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.47
• Publications: 0 publications found

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]

CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

ENSG00000267727 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24825892).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.654G>A	p.Met218Ile	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.759G>A	p.Met253Ile	missense	Exon 1 of 1	NP_001274353.1
	CEBPA	NM_001287435.2		c.612G>A	p.Met204Ile	missense	Exon 1 of 1	NP_001274364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.654G>A	p.Met218Ile	missense	Exon 1 of 1	ENSP00000427514.1
	CEBPA-DT	ENST00000718467.1		n.8C>T		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000267727	ENST00000587312.1	TSL:3	n.357-54C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000575 AC: 6 AN: 1043506 Hom.: 0 Cov.: 21 AF XY: 0.00000401 AC XY: 2 AN XY: 498490

African (AFR) AF: 0.00 AC: 0 AN: 20752

American (AMR) AF: 0.00 AC: 0 AN: 6764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11918

East Asian (EAS) AF: 0.00 AC: 0 AN: 21790

South Asian (SAS) AF: 0.00 AC: 0 AN: 23974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2670

European-Non Finnish (NFE) AF: 0.00000670 AC: 6 AN: 895636

Other (OTH) AF: 0.00 AC: 0 AN: 40112

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148124 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72194

African (AFR) AF: 0.00 AC: 0 AN: 40858

American (AMR) AF: 0.00 AC: 0 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66682

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.059
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.36	T
Polyphen		0.47	P
Vest4		0.40
MutPred		0.20		Gain of sheet (P = 0.0827)
MVP		0.16
ClinPred		0.80	D
GERP RS		4.0
Varity_R		0.71
gMVP		0.24
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs1555742071; hg19: chr19-33792667;