rs957167825

Variant names:

• chr19-33301888-G-A
• rs957167825
• NM_004364.5:c.527C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33301888-G-A
• chr19-33301888-G-C

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.527C>T​(p.Ala176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,302,910 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A176G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.27
• Publications: 5 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18529317).
• BS2: High AC in GnomAdExome4 at 31 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.527C>T	p.Ala176Val	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.632C>T	p.Ala211Val	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.485C>T	p.Ala162Val	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.527C>T	p.Ala176Val	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.430G>A		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+89G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 4 AN: 147894 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000268 AC: 31 AN: 1155016 Hom.: 0 Cov.: 33 AF XY: 0.0000230 AC XY: 13 AN XY: 566336

African (AFR) AF: 0.00 AC: 0 AN: 22696

American (AMR) AF: 0.00 AC: 0 AN: 17026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17054

East Asian (EAS) AF: 0.00 AC: 0 AN: 22116

South Asian (SAS) AF: 0.00 AC: 0 AN: 51048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3086

European-Non Finnish (NFE) AF: 0.0000326 AC: 31 AN: 951812

Other (OTH) AF: 0.00 AC: 0 AN: 44426

GnomAD4 genome AF: 0.0000270 AC: 4 AN: 147894 Hom.: 0 Cov.: 32 AF XY: 0.0000278 AC XY: 2 AN XY: 71968

African (AFR) AF: 0.0000488 AC: 2 AN: 41012

American (AMR) AF: 0.00 AC: 0 AN: 14908

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66348

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Acute myeloid leukemia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.052
Sift	Uncertain	0.013	D
Sift4G	Benign	0.098	T
Polyphen		0.028	B
Vest4		0.077
MutPred		0.28		Loss of helix (P = 0.0072)
MVP		0.16
ClinPred		0.45	T
GERP RS		3.6
Varity_R		0.24
gMVP		0.37
Mutation Taster		=88/12	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: rs957167825; hg19: chr19-33792794; COSMIC: COSV57196390;