Variant chr19-44908774-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000041.4(APOE):c.478C>G(p.Arg160Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.438

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.478C>G	p.Arg160Gly	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.478C>G	p.Arg160Gly	missense_variant	4/4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 linkuse as main transcript	c.478C>G	p.Arg160Gly	missense_variant	3/3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 linkuse as main transcript	c.556C>G	p.Arg186Gly	missense_variant	4/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 linkuse as main transcript	c.478C>G	p.Arg160Gly	missense_variant	4/4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000632

AC:

AN:

158292

Hom.:

AF XY:

0.0000115

AC XY:

AN XY:

86856

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:

0.0000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408050

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696150

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:

9.20e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.7

D;D;.;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.30

MutPred

0.90

Loss of disorder (P = 0.1179);Loss of disorder (P = 0.1179);.;Loss of disorder (P = 0.1179);

MVP

0.98

MPC

1.8

ClinPred

0.98

GERP RS

3.7

Varity_R

0.88

gMVP

0.68

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