19-44908730-G-A

Position:

chr19-44908730-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000041.4(APOE):c.434G>A(p.Gly145Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,560,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.98

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_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30857354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.434G>A	p.Gly145Asp	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.434G>A	p.Gly145Asp	missense_variant	4/4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 linkuse as main transcript	c.434G>A	p.Gly145Asp	missense_variant	3/3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 linkuse as main transcript	c.512G>A	p.Gly171Asp	missense_variant	4/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 linkuse as main transcript	c.434G>A	p.Gly145Asp	missense_variant	4/4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000158

AC:

AN:

158024

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

86226

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:

0.0000426

Gnomad FIN exome

AF:

0.0000648

Gnomad NFE exome

AF:

0.000340

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.000170

AC:

239

AN:

1408146

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

107

AN XY:

695816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000547

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000498

Gnomad4 FIN exome

AF:

0.0000413

Gnomad4 NFE exome

AF:

0.000205

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.000144

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2024

The p.G145D variant (also known as c.434G>A), located in coding exon 3 of the APOE gene, results from a G to A substitution at nucleotide position 434. The glycine at codon 145 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in individual(s) in dyslipidemia cohorts, but clinical details were limited, and it has been seen in conjunction with additional related alterations, including the APOE homozygous ε2 allele (Iron A et al. J Inherit Metab Dis, 1995;18:723-6; Feussner G et al. Hum Mutat, 1998;11:417-23; Civeira F et al. Am Heart J, 1999 Jul;138:156-62; Evans D et al. J Clin Lipidol, 2013 May;7:671-4; Cefalù AB et al. J Clin Lipidol, 2017 Jan;11:272-281.e8; Le R et al. J Investig Med High Impact Case Rep, 2019;7:2324709619877050; Rasmussen KL et al. Alzheimers Dement, 2020 Dec;16:1624-1637; Limonova AS et al. Front Cardiovasc Med, 2020 Jan;7:585779). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial type 3 hyperlipoproteinemia;C0036489:Sea-blue histiocyte syndrome;C1843013:Alzheimer disease 3;C1847200:Alzheimer disease 4;C1863051:Alzheimer disease 2;C1864205:Age related macular degeneration 1;C2673196:Lipoprotein glomerulopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.66

N;N;.;N

REVEL

Uncertain

0.52

Sift

Benign

0.11

T;T;.;T

Sift4G

Benign

0.068

T;T;D;T

Polyphen

1.0

D;.;.;.

Vest4

0.66

MVP

0.94

MPC

1.8

ClinPred

0.19

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.40

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