rs267606662

Positions:

• chr19-44908804-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000041.4(APOE):​c.508G>C​(p.Ala170Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480

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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000041.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32213235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.508G>C	p.Ala170Pro	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.508G>C	p.Ala170Pro	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.508G>C	p.Ala170Pro	missense_variant	3/3	1
APOE	ENST00000434152.5	c.586G>C	p.Ala196Pro	missense_variant	4/4	2
APOE	ENST00000446996.5	c.508G>C	p.Ala170Pro	missense_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.029	D;D;.;D
Sift4G	Benign	0.099	T;T;D;T
Polyphen		0.99	D;.;.;.
Vest4		0.25
MutPred		0.26		Gain of ubiquitination at K175 (P = 0.0516);Gain of ubiquitination at K175 (P = 0.0516);.;Gain of ubiquitination at K175 (P = 0.0516);
MVP		0.92
MPC		1.7
ClinPred		0.37	T
GERP RS		1.4
Varity_R		0.81
gMVP		0.88

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: rs267606662; hg19: chr19-45412061;