NM_004364.5:c.561G>C

Variant names:

• chr19-33301854-C-G
• rs538441046
• NM_004364.5:c.561G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004364.5(CEBPA):​c.561G>C​(p.Pro187Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,277,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: CEBPA NM_004364.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.330
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-33301854-C-G is Benign according to our data. Variant chr19-33301854-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.
• BS2: High AC in GnomAd4 at 54 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.561G>C	p.Pro187Pro	synonymous	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.666G>C	p.Pro222Pro	synonymous	Exon 1 of 1	NP_001274353.1
	CEBPA	NM_001287435.2		c.519G>C	p.Pro173Pro	synonymous	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.561G>C	p.Pro187Pro	synonymous	Exon 1 of 1	ENSP00000427514.1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.396C>G		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+55C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 53 AN: 146532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00445

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000364

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.000698 AC: 30 AN: 42962 AF XY: 0.000818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.000490

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.000768

GnomAD4 exome AF: 0.000344 AC: 389 AN: 1131268 Hom.: 1 Cov.: 32 AF XY: 0.000387 AC XY: 214 AN XY: 553426

African (AFR) AF: 0.00 AC: 0 AN: 21878

American (AMR) AF: 0.000205 AC: 3 AN: 14636

Ashkenazi Jewish (ASJ) AF: 0.000887 AC: 14 AN: 15780

East Asian (EAS) AF: 0.00 AC: 0 AN: 20668

South Asian (SAS) AF: 0.00315 AC: 151 AN: 47978

European-Finnish (FIN) AF: 0.0000412 AC: 1 AN: 24290

Middle Eastern (MID) AF: 0.00204 AC: 6 AN: 2936

European-Non Finnish (NFE) AF: 0.000209 AC: 196 AN: 939746

Other (OTH) AF: 0.000415 AC: 18 AN: 43356

GnomAD4 genome AF: 0.000368 AC: 54 AN: 146642 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 24 AN XY: 71406

African (AFR) AF: 0.0000491 AC: 2 AN: 40706

American (AMR) AF: 0.00 AC: 0 AN: 14824

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3382

East Asian (EAS) AF: 0.000214 AC: 1 AN: 4672

South Asian (SAS) AF: 0.00445 AC: 21 AN: 4714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000379 AC: 25 AN: 65994

Other (OTH) AF: 0.000490 AC: 1 AN: 2040

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000257

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Acute myeloid leukemia (1)
-	-	1	CEBPA-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		0.33
Mutation Taster		=100/0	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: rs538441046; hg19: chr19-33792760;