Variant 19-44909032-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000041.4(APOE):c.736C>T(p.Arg246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000531 in 1,545,348 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: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 1.19

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 Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 19-44909032-C-T is Pathogenic according to our data. Variant chr19-44909032-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17859.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.736C>T	p.Arg246Cys	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9 linkuse as main transcript	c.736C>T	p.Arg246Cys	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000434152.5 linkuse as main transcript			downstream_gene_variant		2		ENSP00000413653

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000416

AC:

AN:

144096

Hom.:

AF XY:

0.0000635

AC XY:

AN XY:

78684

show subpopulations

Gnomad AFR exome

AF:

0.000261

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:

0.0000702

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1393240

Hom.:

Cov.:

AF XY:

0.0000494

AC XY:

AN XY:

688454

show subpopulations

Gnomad4 AFR exome

AF:

0.000345

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:

0.0000499

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000265

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000443

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

APOE2-DUNEDIN

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1991

- -

HYPERLIPOPROTEINEMIA, TYPE IV/V, DUE TO APOE2-DUNEDIN

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

0.097

Eigen_PC

Benign

-0.016

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.0000045

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.81

MVP

0.92

MPC

1.8

ClinPred

0.60

GERP RS

1.1

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.26

gMVP

0.90

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