rs1060502118

Positions:

• chr19-33301819-GC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.22

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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/exons	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	2/2	3

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2023	This variant is also known as 744-745GC>TT. 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). ClinVar contains an entry for this variant (Variation ID: 408745). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

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