NM_004364.5:c.311_313delGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_004364.5(CEBPA):c.311_313delGCG(p.Gly104del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,320,690 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G104G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.85

Publications

1 publications found

Variant links:

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]

CEBPA links:

CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

CEBPA-DT links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004364.5

BP6

Variant 19-33302101-TCGC-T is Benign according to our data. Variant chr19-33302101-TCGC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1009372.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CEBPA	NM_004364.5 link	c.311_313delGCG	p.Gly104del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2 link	c.416_418delGCG	p.Gly139del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2 link	c.269_271delGCG	p.Gly90del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2 link	c.-47_-45delGCG		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CEBPA	ENST00000498907.3 link	c.311_313delGCG	p.Gly104del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
CEBPA-DT	ENST00000718467.1 link	n.46+319_46+321delGCC		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.162_164delCGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000699

AC:

AN:

142978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000491

AC:

AN:

54968

AF XY:

0.000433

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.000843

Gnomad ASJ exome

AF:

0.000677

Gnomad EAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.0000819

Gnomad NFE exome

AF:

0.000471

Gnomad OTH exome

AF:

0.000725

GnomAD4 exome

AF:

0.000138

AC:

162

AN:

1177712

Hom.:

AF XY:

0.000161

AC XY:

AN XY:

571324

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000166

AC:

AN:

24076

American (AMR)

AF:

0.000708

AC:

AN:

15528

Ashkenazi Jewish (ASJ)

AF:

0.000374

AC:

AN:

18726

East Asian (EAS)

AF:

0.0000767

AC:

AN:

26060

South Asian (SAS)

AF:

0.000765

AC:

AN:

41812

European-Finnish (FIN)

AF:

0.000229

AC:

AN:

39328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3340

European-Non Finnish (NFE)

AF:

0.0000925

AC:

AN:

962276

Other (OTH)

AF:

0.000172

AC:

AN:

46566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.241

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000699

AC:

AN:

142978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69706

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

39538

American (AMR)

AF:

0.00

AC:

AN:

14404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

4048

South Asian (SAS)

AF:

0.00

AC:

AN:

3862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65622

Other (OTH)

AF:

0.00

AC:

AN:

2026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:1

May 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with myelodysplastic syndrome and acute myeloid leukemia (PMID: 14726504, 18182175). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.311_313del, results in the deletion of 1 amino acid(s) of the CEBPA protein (p.Gly104del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases

Benign:1

Mar 20, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=83/17

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over