rs1060502119

Variant names:

• chr19-33302236-G-A
• rs1060502119
• NM_004364.5:c.179C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001285829.2(CEBPA):​c.-179C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,341,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CEBPA NM_001285829.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.855
• Publications: 3 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-33302236-G-A is Benign according to our data. Variant chr19-33302236-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408746.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001285829.2. 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.179C>T	p.Thr60Met	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001285829.2		c.-179C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_001272758.1	P49715-3
	CEBPA	NM_001287424.2		c.284C>T	p.Thr95Met	missense	Exon 1 of 1	NP_001274353.1	P49715-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.179C>T	p.Thr60Met	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+437G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000937 AC: 1 AN: 106676 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1341120 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 661340

African (AFR) AF: 0.00 AC: 0 AN: 27144

American (AMR) AF: 0.00 AC: 0 AN: 29540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23364

East Asian (EAS) AF: 0.00 AC: 0 AN: 29598

South Asian (SAS) AF: 0.00 AC: 0 AN: 73586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1050200

Other (OTH) AF: 0.00 AC: 0 AN: 55106

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 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	Pathogenic	0.66
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.85
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.063
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.23		Gain of sheet (P = 0.0221)
MVP		0.45
ClinPred		0.39	T
GERP RS		2.9
PromoterAI		0.0058	Neutral
Varity_R		0.21
gMVP		0.39
Mutation Taster		=79/21	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: rs1060502119; hg19: chr19-33793142;