rs7412

Positions:

• chr19-44908822-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Strong BA1

The NM_000041.4(APOE):​c.526C>T​(p.Arg176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,540,810 control chromosomes in the GnomAD database, including 4,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.078 (546 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4063 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: drug response reviewed by expert panel P:1 U:1 B:4 O:4
• Conservation: PhyloP100: 0.906

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 Benign. Variant got -14 ACMG points.

• PM1: In a helix (size 31) in uniprot entity APOE_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000041.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021114647).
• BP6: Variant 19-44908822-C-T is Benign according to our data. Variant chr19-44908822-C-T is described in ClinVar as [drug_response]. Clinvar id is 17848.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, risk_factor=1, Likely_benign=1, other=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.526C>T	p.Arg176Cys	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.526C>T	p.Arg176Cys	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.526C>T	p.Arg176Cys	missense_variant	3/3	1
APOE	ENST00000434152.5	c.604C>T	p.Arg202Cys	missense_variant	4/4	2
APOE	ENST00000446996.5	c.526C>T	p.Arg176Cys	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11838 AN: 152004 Hom.: 546 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0761

GnomAD3 exomes AF: 0.0615 AC: 8425 AN: 136984 Hom.: 315 AF XY: 0.0613 AC XY: 4615 AN XY: 75288

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.0742

Gnomad SAS exome AF: 0.0419

Gnomad FIN exome AF: 0.0454

Gnomad NFE exome AF: 0.0751

Gnomad OTH exome AF: 0.0608

GnomAD4 exome AF: 0.0738 AC: 102550 AN: 1388698 Hom.: 4063 Cov.: 34 AF XY: 0.0726 AC XY: 49779 AN XY: 685974

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0319

Gnomad4 ASJ exome AF: 0.0748

Gnomad4 EAS exome AF: 0.0577

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.0499

Gnomad4 NFE exome AF: 0.0782

Gnomad4 OTH exome AF: 0.0703

GnomAD4 genome AF: 0.0778 AC: 11840 AN: 152112 Hom.: 546 Cov.: 32 AF XY: 0.0745 AC XY: 5538 AN XY: 74372

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.0801

Gnomad4 SAS AF: 0.0373

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0794

Gnomad4 OTH AF: 0.0772

Alfa AF: 0.0831 Hom.: 1411

Bravo AF: 0.0781

TwinsUK AF: 0.0917 AC: 340

ALSPAC AF: 0.0924 AC: 356

ESP6500AA AF: 0.0867 AC: 271

ESP6500EA AF: 0.0562 AC: 356

ExAC AF: 0.0360 AC: 3513

Asia WGS AF: 0.0820 AC: 285 AN: 3460

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
risk factor, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	APOE: PM5, BS1, BS2 -

Familial type 3 hyperlipoproteinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

atorvastatin response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Warfarin response Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.93	A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.012	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.28
MPC		1.9
ClinPred		0.031	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.61

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: rs7412; hg19: chr19-45412079; COSMIC: COSV52986153; COSMIC: COSV52986153;