NM_004364.5:c.305_313dupGCGGCGGCG

Variant names:

• chr19-33302101-T-TCGCCGCCGC
• rs780345232
• NM_004364.5:c.305_313dupGCGGCGGCG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3

The NM_004364.5(CEBPA):​c.305_313dupGCGGCGGCG​(p.Gly102_Gly104dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,322,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CEBPA NM_004364.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.85

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004364.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.305_313dupGCGGCGGCG	p.Gly102_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.410_418dupGCGGCGGCG	p.Gly137_Gly139dup	conservative_inframe_insertion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.263_271dupGCGGCGGCG	p.Gly88_Gly90dup	conservative_inframe_insertion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.-53_-45dupGCGGCGGCG		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.305_313dupGCGGCGGCG	p.Gly102_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.*161_*162insCGCCGCCGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 4 AN: 142988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000694

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 AF: 0.00000170 AC: 2 AN: 1179150 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 572106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000280 AC: 4 AN: 142988 Hom.: 0 Cov.: 32 AF XY: 0.0000574 AC XY: 4 AN XY: 69714

Gnomad4 AFR AF: 0.0000759

Gnomad4 AMR AF: 0.0000694

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame duplication of 3 amino acids in a repetitive region with no known function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Acute myeloid leukemia Uncertain:1

Oct 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.305_313dup, results in the insertion of 3 amino acid(s) of the CEBPA protein (p.Gly102_Gly104dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 937655). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs780345232; hg19: chr19-33793007;