chr19-44908684-T-C

Position:

chr19-44908684-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5BP4BA1

The NM_000041.4(APOE):c.388T>C(p.Cys130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,567,892 control chromosomes in the GnomAD database, including 17,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars).

Frequency

Genomes: 𝑓 0.16 ( 2010 hom., cov: 32)

Exomes 𝑓: 0.15 ( 15700 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:6U:2O:4

Conservation

PhyloP100: 0.840

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 Benign. Variant got -8 ACMG points.

PP5

Variant 19-44908684-T-C is Pathogenic according to our data. Variant chr19-44908684-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other, risk_factor]. Clinvar id is 17864.We mark this variant Likely_pathogenic, oryginal submissions are: {other=1, Likely_pathogenic=2, risk_factor=2, Uncertain_significance=2, Pathogenic=1}. Variant chr19-44908684-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0037242472). . Strength limited to SUPPORTING due to the PP5.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.388T>C	p.Cys130Arg	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
APOE	ENST00000252486.9 linkuse as main transcript	c.388T>C	p.Cys130Arg	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000425718.1 linkuse as main transcript	c.388T>C	p.Cys130Arg	missense_variant	3/3	1		ENSP00000410423
APOE	ENST00000434152.5 linkuse as main transcript	c.466T>C	p.Cys156Arg	missense_variant	4/4	2		ENSP00000413653
APOE	ENST00000446996.5 linkuse as main transcript	c.388T>C	p.Cys130Arg	missense_variant	4/4	2		ENSP00000413135

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23875

AN:

151972

Hom.:

1998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.0975

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.0673

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.138

AC:

23502

AN:

169692

Hom.:

1663

AF XY:

0.136

AC XY:

12553

AN XY:

92210

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.115

Gnomad EAS exome

AF:

0.0874

Gnomad SAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.209

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.148

AC:

208931

AN:

1415800

Hom.:

15700

Cov.:

AF XY:

0.146

AC XY:

102105

AN XY:

700502

show subpopulations

Gnomad4 AFR exome

AF:

0.227

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.0979

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.157

AC:

23933

AN:

152092

Hom.:

2010

Cov.:

AF XY:

0.161

AC XY:

11948

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.216

Gnomad4 AMR

AF:

0.113

Gnomad4 ASJ

AF:

0.119

Gnomad4 EAS

AF:

0.0977

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.195

Gnomad4 NFE

AF:

0.138

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.0744

Hom.:

502

Bravo

AF:

0.155

TwinsUK

AF:

0.140

AC:

518

ALSPAC

AF:

0.154

AC:

593

ESP6500AA

AF:

0.189

AC:

808

ESP6500EA

AF:

0.117

AC:

961

ExAC

AF:

0.100

AC:

11382

Asia WGS

AF:

0.171

AC:

597

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other; risk factor

Submissions summary: Pathogenic:6Uncertain:2Other:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Other:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
risk factor, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Alzheimer disease 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 27, 2022	- -
Established risk allele, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for Alzheimer's Disease. -

Alzheimer disease

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jun 27, 2019	- -
Established risk allele, no assertion criteria provided	research	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for Alzheimer's Disease. -

Alzheimer disease 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 24, 2020

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM4. This variant was detected in homozygous state. -

Lipoprotein glomerulopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Warfarin response

Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

Primary degenerative dementia of the Alzheimer type, presenile onset

Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 16, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.099

T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.24

T;T;T;T

MetaRNN

Benign

0.0037

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

4.4

N;N;.;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;.;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.051

MPC

1.1

ClinPred

0.00022

GERP RS

3.0

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.0

Varity_R

0.21

gMVP

0.59

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