chr19-44906643-G-A

Variant names:

• chr19-44906643-G-A
• rs1969812567
• NM_000041.4:c.19G>A

Variant summary

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

The NM_000041.4(APOE):​c.19G>A​(p.Ala7Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27291474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.19G>A	p.Ala7Thr	missense_variant	Exon 2 of 4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.19G>A	p.Ala7Thr	missense_variant	Exon 2 of 4	1	NM_000041.4	ENSP00000252486.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.92	N;N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.15	T;T;.;T
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.88	P;.;.;.
Vest4		0.21
MutPred		0.45		Loss of stability (P = 0.0428);Loss of stability (P = 0.0428);.;Loss of stability (P = 0.0428);
MVP		0.95
MPC		0.60
ClinPred		0.18	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.038
gMVP		0.52

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: rs1969812567; hg19: chr19-45409900;