rs998501847

Variant names:

• chr19-33301868-G-A
• rs998501847
• NM_004364.5:c.547C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33301868-G-A
• chr19-33301868-G-T
• chr19-33301868-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_004364.5(CEBPA):​c.547C>T​(p.Pro183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000529 in 1,324,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/22 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. P183T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.51
• Publications: 1 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14944807).
• BP6: Variant 19-33301868-G-A is Benign according to our data. Variant chr19-33301868-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 565564.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.547C>T	p.Pro183Ser	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.652C>T	p.Pro218Ser	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.505C>T	p.Pro169Ser	missense	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.547C>T	p.Pro183Ser	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.410G>A		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+69G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000425 AC: 5 AN: 1176062 Hom.: 0 Cov.: 33 AF XY: 0.00000694 AC XY: 4 AN XY: 576090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000428 AC: 1 AN: 23354

American (AMR) AF: 0.00 AC: 0 AN: 16978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17862

East Asian (EAS) AF: 0.00 AC: 0 AN: 24260

South Asian (SAS) AF: 0.00 AC: 0 AN: 50566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3184

European-Non Finnish (NFE) AF: 0.00000414 AC: 4 AN: 966020

Other (OTH) AF: 0.00 AC: 0 AN: 46126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000244 AC: 1 AN: 41048

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9188

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

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66382

Other (OTH) AF: 0.00 AC: 0 AN: 2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.019
Sift	Benign	0.075	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.25
MutPred		0.24		Loss of catalytic residue at P183 (P = 0.005)
MVP		0.14
ClinPred		0.11	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.35
Mutation Taster		=84/16	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: rs998501847; hg19: chr19-33792774;