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GeneBe

rs429358

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP5BP4BA1

The NM_000041(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 0.157 in 151972 control chromosomes in the gnomAD Genomes database, including 1998 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity,other,risk factor (ā˜…).

Frequency

Genomes: š‘“ 0.16 ( 1998 hom., cov: 32)
Exomes š‘“: 0.14 ( 1663 hom. )

Consequence

APOE
NM_000041 missense

Scores

1
17

Clinical Significance

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

Conservation

PhyloP100: 0.840

Links

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
?
In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000041
PP5
?
Variant 19:44908684-T>C is Pathogenic according to our data. Variant chr19-44908684-T-C is described in ClinVar as [Conflicting_interpretations_of_pathogenicity, other, risk_factor]. Clinvar id is 17864. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, risk_factor=2, Likely_pathogenic=2, Uncertain_significance=2, other=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
?
GnomAd 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 UniProt
APOENM_000041.4 linkuse as main transcriptc.388T>C p.Cys130Arg missense_variant 4/4 ENST00000252486.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOEENST00000252486.9 linkuse as main transcriptc.388T>C p.Cys130Arg missense_variant 4/41 NM_000041.4 P1
APOEENST00000425718.1 linkuse as main transcriptc.388T>C p.Cys130Arg missense_variant 3/31
APOEENST00000434152.5 linkuse as main transcriptc.466T>C p.Cys156Arg missense_variant 4/42
APOEENST00000446996.5 linkuse as main transcriptc.388T>C p.Cys130Arg missense_variant 4/42

Frequencies

GnomAD3 genomes
AF:
0.157
AC:
23875
AN:
151972
Hom.:
1998
Cov.:
32
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
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
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 interpretations of pathogenicity; other; risk factor
Submissions summary: Pathogenic:6Uncertain:2Other:4
Revision: criteria provided, conflicting interpretations
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1Other:2
other, criteria provided, single submitterclinical testingEurofins 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).
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022- -
risk factor, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 29, 2022- -
Alzheimer disease 2 Pathogenic:2
Established risk allele, no assertion criteria providedclinical testingDepartment 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 Ɨ 10ā€“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 =1.02ƗEāˆ’08, OR=0.6, 95% CI: 4.20ā€“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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 27, 2022- -
Alzheimer disease Pathogenic:2
Established risk allele, no assertion criteria providedresearchDepartment 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 Ɨ 10ā€“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 =1.02ƗEāˆ’08, OR=0.6, 95% CI: 4.20ā€“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. -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Laboratory, M Health Fairview: University of MinnesotaJun 27, 2019- -
Alzheimer disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaMar 24, 2020This 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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Warfarin response Other:1
drug response, no assertion criteria providedresearchPharmacogenomics Lab, Chungbuk National UniversityAug 31, 2010- likely responsive
Primary degenerative dementia of the Alzheimer type, presenile onset Other:1
risk factor, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 16, 2019proposed 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
T
BayesDel_noAF
Benign
-0.31
Cadd
Benign
17
Dann
Benign
0.22
DEOGEN2
Benign
0.099
T;T;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.24
T;T;T;T
MetaRNN
Benign
0.0037
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.5
N;.;.;.
MutationTaster
Benign
1.0
P
PrimateAI
Uncertain
0.55
T
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
T
GERP RS
3.0
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
4.0
Varity_R
0.21
gMVP
0.59

Splicing

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.

Other links and lift over

dbSNP: rs429358; hg19: chr19-45411941; COSMIC: COSV52985231; COSMIC: COSV52985231;