19-44908783-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000041.4(APOE):c.487C>T(p.Arg163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,557,986 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0064 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 11 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:6

Conservation

PhyloP100: 1.57

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 Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0120640695).

BP6

Variant 19-44908783-C-T is Benign according to our data. Variant chr19-44908783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17851.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=5}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (978/152238) while in subpopulation AFR AF= 0.0209 (869/41564). AF 95% confidence interval is 0.0198. There are 15 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.487C>T	p.Arg163Cys	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.487C>T	p.Arg163Cys	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 3 of 3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.565C>T	p.Arg189Cys	missense_variant	Exon 4 of 4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 4 of 4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

978

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00142

AC:

220

AN:

154854

Hom.:

AF XY:

0.000929

AC XY:

AN XY:

85004

show subpopulations

Gnomad AFR exome

AF:

0.0222

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000854

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000817

Gnomad OTH exome

AF:

0.000685

GnomAD4 exome

AF:

0.000684

AC:

961

AN:

1405748

Hom.:

Cov.:

AF XY:

0.000593

AC XY:

412

AN XY:

694984

show subpopulations

Gnomad4 AFR exome

AF:

0.0211

Gnomad4 AMR exome

AF:

0.00227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000873

Gnomad4 FIN exome

AF:

0.0000448

Gnomad4 NFE exome

AF:

0.0000635

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00642

AC:

978

AN:

152238

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0209

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00785

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.000262

AC:

ExAC

AF:

0.00123

AC:

134

Asia WGS

AF:

0.00145

AC:

AN:

3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	This variant is associated with the following publications: (PMID: 24239320, 26377243, 3243553, 22069485, 20981092, 11500500, 24507774) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 17, 2023	BS1, BS2, PS3 -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Familial type 3 hyperlipoproteinemia

Pathogenic:2

Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000041.2:c.487C>T in the APOE gene has an allele frequency of 0.021 in African subpopulation in the gnomAD database. The p.Arg163Cys (NM_000041.2:c.487C>T) variant has been reported to be associated with type III hyperlipoproteinemia (PMID: 25502880; 26802169). In vitro functional studies suggest that the p.Arg163Cys variant may affect protein function (PMID: 26802169). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1988	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2021	- -
Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.069, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

APOE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;T;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

M;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.9

D;D;.;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.49

MVP

0.98

MPC

1.9

ClinPred

0.037

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.72

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