Variant rs121918394 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000041.4(APOE):c.490A>C(p.Lys164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.07

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 9 ACMG points.

PM1

In a helix (size 31) in uniprot entity APOE_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000041.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 19-44908786-A-C is Pathogenic according to our data. Variant chr19-44908786-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17858.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-44908786-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.490A>C	p.Lys164Gln	missense_variant	4/4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 linkuse as main transcript	c.490A>C	p.Lys164Gln	missense_variant	4/4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 linkuse as main transcript	c.490A>C	p.Lys164Gln	missense_variant	3/3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 linkuse as main transcript	c.568A>C	p.Lys190Gln	missense_variant	4/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 linkuse as main transcript	c.490A>C	p.Lys164Gln	missense_variant	4/4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000651

AC:

AN:

153504

Hom.:

AF XY:

0.0000119

AC XY:

AN XY:

84244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1404912

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694496

show subpopulations

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:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type III, due to APOE2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.86

D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

D;D;.;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0070

D;D;.;D

Sift4G

Benign

0.19

T;D;T;D

Polyphen

1.0

D;.;.;.

Vest4

0.78

MutPred

0.89

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;Gain of helix (P = 0.1736);

MVP

0.93

MPC

1.6

ClinPred

0.93

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over