19-33302204-C-T

Variant names:

• chr19-33302204-C-T
• rs1555742260
• NM_004364.5:c.211G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004364.5(CEBPA):​c.211G>A​(p.Ala71Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.840

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3371215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.211G>A	p.Ala71Thr	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.316G>A	p.Ala106Thr	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.169G>A	p.Ala57Thr	missense_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.-147G>A		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.211G>A	p.Ala71Thr	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345414 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 663442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.50e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

Jan 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CEBPA-related disease. This sequence change replaces alanine with threonine at codon 71 of the CEBPA protein (p.Ala71Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.14	T
Polyphen		0.38	B
Vest4		0.21
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.34
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.42
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs1555742260; hg19: chr19-33793110;