rs1555742114

Variant names:

• chr19-33301846-G-A
• rs1555742114
• NM_004364.5:c.569C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33301846-G-A
• chr19-33301846-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001287424.2(CEBPA):​c.674C>T​(p.Ser225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,313,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S225P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CEBPA NM_001287424.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0890
• 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]

ENSG00000267727 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08952269).
• BP6: Variant 19-33301846-G-A is Benign according to our data. Variant chr19-33301846-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526806.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287424.2. 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.569C>T	p.Ser190Leu	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.674C>T	p.Ser225Leu	missense	Exon 1 of 1	NP_001274353.1
	CEBPA	NM_001287435.2		c.527C>T	p.Ser176Leu	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.569C>T	p.Ser190Leu	missense	Exon 1 of 1	ENSP00000427514.1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.388G>A		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+47G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148072 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: 0.00

Gnomad OTH AF: 0.000491

GnomAD4 exome AF: 0.00000343 AC: 4 AN: 1165692 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 569922

African (AFR) AF: 0.00 AC: 0 AN: 23120

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16990

East Asian (EAS) AF: 0.00 AC: 0 AN: 24256

South Asian (SAS) AF: 0.00 AC: 0 AN: 47844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3144

European-Non Finnish (NFE) AF: 0.00000416 AC: 4 AN: 962586

Other (OTH) AF: 0.00 AC: 0 AN: 45886

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72066

African (AFR) AF: 0.00 AC: 0 AN: 41002

American (AMR) AF: 0.00 AC: 0 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9176

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66442

Other (OTH) AF: 0.000491 AC: 1 AN: 2036

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.089
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.068
Sift	Benign	0.18	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.36		Loss of glycosylation at S190 (P = 1e-04)
MVP		0.19
ClinPred		0.074	T
GERP RS		-5.2
Varity_R		0.15
gMVP		0.23
Mutation Taster		=90/10	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: rs1555742114; hg19: chr19-33792752;