NM_000041.4:c.526C>T

Variant names:

• chr19-44908822-C-T
• rs7412
• NM_000041.4:c.526C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176P) has been classified as Uncertain significance.

• 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:5 O:4
• Conservation: PhyloP100: 0.906
• Publications: 3058 publications found

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 Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a helix (size 31) in uniprot entity APOE_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000041.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1391 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021114647).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.526C>T	p.Arg176Cys	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.604C>T	p.Arg202Cys	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.526C>T	p.Arg176Cys	missense	Exon 4 of 4	NP_001289618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.526C>T	p.Arg176Cys	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.526C>T	p.Arg176Cys	missense	Exon 3 of 3	ENSP00000410423.1
	APOE	ENST00000864831.1		c.580C>T	p.Arg194Cys	missense	Exon 5 of 5	ENSP00000534890.1

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

GnomAD2 exomes AF: 0.0615 AC: 8425 AN: 136984 AF XY: 0.0613

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 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

African (AFR) AF: 0.107 AC: 3392 AN: 31704

American (AMR) AF: 0.0319 AC: 1151 AN: 36044

Ashkenazi Jewish (ASJ) AF: 0.0748 AC: 1873 AN: 25038

East Asian (EAS) AF: 0.0577 AC: 2080 AN: 36054

South Asian (SAS) AF: 0.0419 AC: 3331 AN: 79482

European-Finnish (FIN) AF: 0.0499 AC: 1873 AN: 37554

Middle Eastern (MID) AF: 0.0588 AC: 270 AN: 4592

European-Non Finnish (NFE) AF: 0.0782 AC: 84522 AN: 1080474

Other (OTH) AF: 0.0703 AC: 4058 AN: 57756

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

African (AFR) AF: 0.104 AC: 4337 AN: 41520

American (AMR) AF: 0.0419 AC: 640 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3470

East Asian (EAS) AF: 0.0801 AC: 414 AN: 5166

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4832

European-Finnish (FIN) AF: 0.0419 AC: 443 AN: 10580

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0794 AC: 5397 AN: 67946

Other (OTH) AF: 0.0772 AC: 163 AN: 2112

Alfa AF: 0.0797 Hom.: 1660

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

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (5)
-	-	2	not specified (2)
1	-	-	Familial type 3 hyperlipoproteinemia (1)
-	-	1	Hypercholesterolemia (1)
-	-	-	atorvastatin response - Efficacy (1)
-	-	-	Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.91
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	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
Mutation Taster		=43/57	polymorphism (auto)

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

Other links and lift over

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