19-44907841-A-C

Variant summary

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

The NM_000041.4(APOE):c.125A>C(p.Gln42Pro) 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: APOE NM_000041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

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	UniProt
APOE	NM_000041.4	c.125A>C	p.Gln42Pro	missense_variant	3/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.125A>C	p.Gln42Pro	missense_variant	3/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.125A>C	p.Gln42Pro	missense_variant	2/3	1
APOE	ENST00000434152.5	c.203A>C	p.Gln68Pro	missense_variant	3/4	2
APOE	ENST00000446996.5	c.125A>C	p.Gln42Pro	missense_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The p.Q42P variant (also known as c.125A>C), located in coding exon 2 of the APOE gene, results from an A to C substitution at nucleotide position 125. The glutamine at codon 42 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.025	D;D;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.56
MutPred		0.57		Gain of glycosylation at Q42 (P = 0.0595);Gain of glycosylation at Q42 (P = 0.0595);.;Gain of glycosylation at Q42 (P = 0.0595);
MVP		0.97
MPC		1.7
ClinPred		0.75	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45411098;