Genetic Variant NM_004364.5:c.541T>A (chr19-33301874-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004364.5(CEBPA):c.541T>A(p.Tyr181Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Variant links:

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 links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26324278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.541T>A	p.Tyr181Asn	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.646T>A	p.Tyr216Asn	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.499T>A	p.Tyr167Asn	missense_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.184T>A	p.Tyr62Asn	missense_variant	Exon 1 of 1		NP_001272758.1	P49715-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3 link	c.541T>A	p.Tyr181Asn	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1		P49715-1
ENSG00000267727	ENST00000587312.1 link	n.416A>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141984

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000697

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000704

AC:

AN:

142128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69122

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000696

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.25

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.3

REVEL

Benign

0.054

Sift

Uncertain

0.024

Sift4G

Uncertain

0.027

Polyphen

0.94

Vest4

0.31

MutPred

0.19

Loss of phosphorylation at Y181 (P = 0.0077);

MVP

0.27

ClinPred

0.31

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over