rs1060502118

Variant names:

• chr19-33301819-GC-AA
• rs1060502118
• NM_004364.5:c.595_596delGCinsTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004364.5(CEBPA):​c.595_596delGCinsTT​(p.Ala199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000371 in 1 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. A199T) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.000037 Genomes: not found (cov: 32)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.22
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.595_596delGCinsTT	p.Ala199Leu	missense_variant		ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.700_701delGCinsTT	p.Ala234Leu	missense_variant			NP_001274353.1
CEBPA	NM_001287435.2	c.553_554delGCinsTT	p.Ala185Leu	missense_variant			NP_001274364.1
CEBPA	NM_001285829.2	c.238_239delGCinsTT	p.Ala80Leu	missense_variant			NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.595_596delGCinsTT	p.Ala199Leu	missense_variant		6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.361_362delGCinsAA		non_coding_transcript_exon_variant	Exon 2 of 2	3
CEBPA-DT	ENST00000718467.1	n.46+20_46+21delGCinsAA		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.0000371 AC: 1 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia Uncertain:2

Sep 15, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 408745). This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 199 of the CEBPA protein (p.Ala199Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 18768433). This variant is also known as 744-745GC>TT. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Inborn genetic diseases Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595_596delGCinsTT variant (also known as p.A199L), located in coding exon 1 of the CEBPA gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 595 to 596. This results in the substitution of the alanine residue for a leucine residue at codon 199, an amino acid with similar properties. This variant was reported in an individual with acute myeloid leukemia (Bienz M et al. Clin Cancer Res, 2005 Feb;11:1416-24). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

May 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this variant does not alter protein structure/function; Observed in a patient with acute myeloid leukemia (PMID: 18768433); This variant is associated with the following publications: (PMID: 21455213, 18768433) -

CEBPA-related disorder Uncertain:1

Mar 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEBPA c.595_596delinsTT variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is classified as variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408745/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

Splicing

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

Other links and lift over

dbSNP: rs1060502118; hg19: chr19-33792725; COSMIC: COSV57197283;