rs121918397

Positions:

• chr19-44908784-G-A
• chr19-44908784-G-C
• chr19-44908784-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PP3_Strong PP5_Moderate

The NM_000041.4(APOE):​c.488G>A​(p.Arg163His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000712 in 1,405,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.869

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 31) in uniprot entity APOE_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000041.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 19-44908784-G-A is Pathogenic according to our data. Variant chr19-44908784-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17865.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.488G>A	p.Arg163His	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.488G>A	p.Arg163His	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000425718.1	c.488G>A	p.Arg163His	missense_variant	3/3	1		ENSP00000410423
APOE	ENST00000434152.5	c.566G>A	p.Arg189His	missense_variant	4/4	2		ENSP00000413653
APOE	ENST00000446996.5	c.488G>A	p.Arg163His	missense_variant	4/4	2		ENSP00000413135

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000648 AC: 1 AN: 154258 Hom.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 84626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000830

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000712 AC: 10 AN: 1405464 Hom.: 0 Cov.: 33 AF XY: 0.0000101 AC XY: 7 AN XY: 694802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000217

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial type 3 hyperlipoproteinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1990

- -

Lipoprotein glomerulopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.64; 3Cnet: 0.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with APOE related disorder (ClinVar ID: VCV000017865 / PMID: 15256764). Different missense changes at the same codon (p.Arg163Cys, p.Arg163Pro) have been reported to be associated with APOE related disorder (ClinVar ID: VCV000017851, VCV000017879 / PMID: 3243553, 9176854). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	0.59	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Uncertain	0.64
Sift	Benign	0.068	T;T;.;T
Sift4G	Benign	0.079	T;T;T;T
Polyphen		0.66	P;.;.;.
Vest4		0.27
MutPred		0.93		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);.;Loss of solvent accessibility (P = 0.1077);
MVP		0.96
MPC		0.98
ClinPred		0.72	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.60

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: rs121918397; hg19: chr19-45412041;