19-44908784-G-A

Position:

chr19-44908784-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate

The ENST00000252486.9(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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

APOE
ENST00000252486.9 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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000252486.9

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-44908784-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 17879.Status of the report is no_assertion_criteria_provided, 0 stars.

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 linkuse as main transcript	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
APOE	ENST00000252486.9 linkuse as main transcript	c.488G>A	p.Arg163His	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000425718.1 linkuse as main transcript	c.488G>A	p.Arg163His	missense_variant	3/3	1		ENSP00000410423
APOE	ENST00000434152.5 linkuse as main transcript	c.566G>A	p.Arg189His	missense_variant	4/4	2		ENSP00000413653
APOE	ENST00000446996.5 linkuse as main transcript	c.488G>A	p.Arg163His	missense_variant	4/4	2		ENSP00000413135

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

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

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;.;.;.

MutationTaster

Benign

0.59

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