Variant 19-44908751-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000041.4(APOE):c.455G>T(p.Arg152Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,102 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a repeat 4 (size 21) in uniprot entity APOE_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000041.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-44908751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17874.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.455G>T	p.Arg152Leu	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
APOE	ENST00000252486.9 linkuse as main transcript	c.455G>T	p.Arg152Leu	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1 linkuse as main transcript	c.455G>T	p.Arg152Leu	missense_variant	3/3	1
APOE	ENST00000434152.5 linkuse as main transcript	c.533G>T	p.Arg178Leu	missense_variant	4/4	2
APOE	ENST00000446996.5 linkuse as main transcript	c.455G>T	p.Arg152Leu	missense_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696082

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;T;.;.

Eigen

Benign

0.050

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.68

D;D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.0

D;D;.;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.42

MutPred

0.61

Loss of disorder (P = 0.0372);Loss of disorder (P = 0.0372);.;Loss of disorder (P = 0.0372);

MVP

0.98

MPC

1.7

ClinPred

0.99

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.80

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over