Genetic Variant NM_000041.4:c.487C>T (chr19-44908783-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1PM5PP2BP4_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163P) has been classified as Pathogenic.

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:7

Conservation

PhyloP100: 1.57

Publications

50 publications found

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

APOE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000041.4

PM5

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

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=0.0120640695).

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 VariationId is 17851.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR,Unknown gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOE	NM_000041.4	MANE Select	c.487C>T	p.Arg163Cys	missense	Exon 4 of 4	NP_000032.1	A0A0S2Z3D5
APOE	NM_001302688.2		c.565C>T	p.Arg189Cys	missense	Exon 4 of 4	NP_001289617.1
APOE	NM_001302689.2		c.487C>T	p.Arg163Cys	missense	Exon 4 of 4	NP_001289618.1	P02649

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOE	ENST00000252486.9	TSL:1 MANE Select	c.487C>T	p.Arg163Cys	missense	Exon 4 of 4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1	TSL:1	c.487C>T	p.Arg163Cys	missense	Exon 3 of 3	ENSP00000410423.1	E7ERP7
APOE	ENST00000864831.1		c.541C>T	p.Arg181Cys	missense	Exon 5 of 5	ENSP00000534890.1

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

GnomAD2 exomes

AF:

0.00142

AC:

220

AN:

154854

AF XY:

0.000929

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 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

African (AFR)

AF:

0.0211

AC:

680

AN:

32258

American (AMR)

AF:

0.00227

AC:

AN:

37060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

36794

South Asian (SAS)

AF:

0.0000873

AC:

AN:

80202

European-Finnish (FIN)

AF:

0.0000448

AC:

AN:

44668

Middle Eastern (MID)

AF:

0.00101

AC:

AN:

4936

European-Non Finnish (NFE)

AF:

0.0000635

AC:

AN:

1086388

Other (OTH)

AF:

0.00196

AC:

114

AN:

58268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00642

AC:

978

AN:

152238

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0209

AC:

869

AN:

41564

American (AMR)

AF:

0.00543

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67988

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00142

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Familial type 3 hyperlipoproteinemia (2)

not specified (2)

Alzheimer disease 2 (1)

APOE-related disorder (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

PhyloP100

1.6

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

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

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over