Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBS1_SupportingBS2

The NM_000041.4(APOE):c.761T>A(p.Val254Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,562,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 2 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1B:2

Conservation

PhyloP100: 0.0590

Publications

18 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: 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

APOE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) 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=0.034093946).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000473 (72/152198) while in subpopulation NFE AF = 0.000765 (52/67976). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 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
APOE	NM_000041.4	MANE Select	c.761T>A	p.Val254Glu	missense	Exon 4 of 4	NP_000032.1
APOE	NM_001302688.2		c.839T>A	p.Val280Glu	missense	Exon 4 of 4	NP_001289617.1
APOE	NM_001302689.2		c.761T>A	p.Val254Glu	missense	Exon 4 of 4	NP_001289618.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOE	ENST00000252486.9	TSL:1 MANE Select	c.761T>A	p.Val254Glu	missense	Exon 4 of 4	ENSP00000252486.3
APOE	ENST00000425718.1	TSL:1	c.*103T>A		downstream_gene	N/A	ENSP00000410423.1
APOE	ENST00000434152.5	TSL:2	c.*32T>A		downstream_gene	N/A	ENSP00000413653.2

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000452

AC:

AN:

165832

AF XY:

0.000494

show subpopulations

Gnomad AFR exome

AF:

0.000214

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000215

Gnomad NFE exome

AF:

0.000999

Gnomad OTH exome

AF:

0.000214

GnomAD4 exome

AF:

0.000659

AC:

929

AN:

1410160

Hom.:

Cov.:

AF XY:

0.000643

AC XY:

449

AN XY:

698452

show subpopulations

African (AFR)

AF:

0.000154

AC:

AN:

32438

American (AMR)

AF:

0.0000265

AC:

AN:

37666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25370

East Asian (EAS)

AF:

0.00

AC:

AN:

37112

South Asian (SAS)

AF:

0.00

AC:

AN:

81282

European-Finnish (FIN)

AF:

0.0000742

AC:

AN:

40430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.000829

AC:

905

AN:

1091808

Other (OTH)

AF:

0.000255

AC:

AN:

58718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000473

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000765

AC:

AN:

67976

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000463

Hom.:

Bravo

AF:

0.000427

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.000431

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial type 3 hyperlipoproteinemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.6

PhyloP100

0.059

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.26

Sift

Uncertain

0.010

Sift4G

Uncertain

0.019

Polyphen

0.89

Vest4

0.43

MVP

0.90

MPC

1.8

ClinPred

0.12

GERP RS

3.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.33

gMVP

0.82

Mutation Taster

=88/12

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000041.4:c.761T>A

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over