rs121918397

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PP3_StrongPP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.869

Variant links:

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]

APOE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a repeat 4 (size 21) 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 rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.488G>A	p.Arg163His	missense_variant	Exon 4 of 4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.488G>A	p.Arg163His	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.488G>A	p.Arg163His	missense_variant	Exon 3 of 3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.566G>A	p.Arg189His	missense_variant	Exon 4 of 4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.488G>A	p.Arg163His	missense_variant	Exon 4 of 4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000648

AC:

AN:

154258

Hom.:

AF XY:

0.0000118

AC XY:

AN XY:

84626

show subpopulations

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:

AN:

1405464

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

694802

show subpopulations

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.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial type 3 hyperlipoproteinemia

Pathogenic:1

Nov 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lipoprotein glomerulopathy

Pathogenic:1

May 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.9

L;.;.;.

PrimateAI

Uncertain

0.57

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over