19-44908783-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000041.4(APOE):c.487C>T(p.Arg163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,557,986 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0064 ( 15 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 11 hom. )
Consequence
APOE
NM_000041.4 missense
NM_000041.4 missense
Scores
4
10
4
Clinical Significance
Conservation
PhyloP100: 1.57
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 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
BP4
Computational evidence support a benign effect (MetaRNN=0.0120640695).
BP6
Variant 19-44908783-C-T is Benign according to our data. Variant chr19-44908783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17851.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=5}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (978/152238) while in subpopulation AFR AF= 0.0209 (869/41564). AF 95% confidence interval is 0.0198. There are 15 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 15 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOE | NM_000041.4 | c.487C>T | p.Arg163Cys | missense_variant | Exon 4 of 4 | ENST00000252486.9 | NP_000032.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOE | ENST00000252486.9 | c.487C>T | p.Arg163Cys | missense_variant | Exon 4 of 4 | 1 | NM_000041.4 | ENSP00000252486.3 | ||
APOE | ENST00000425718.1 | c.487C>T | p.Arg163Cys | missense_variant | Exon 3 of 3 | 1 | ENSP00000410423.1 | |||
APOE | ENST00000434152.5 | c.565C>T | p.Arg189Cys | missense_variant | Exon 4 of 4 | 2 | ENSP00000413653.2 | |||
APOE | ENST00000446996.5 | c.487C>T | p.Arg163Cys | missense_variant | Exon 4 of 4 | 2 | ENSP00000413135.1 |
Frequencies
GnomAD3 genomes AF: 0.00643 AC: 978AN: 152126Hom.: 15 Cov.: 32
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GnomAD3 exomes AF: 0.00142 AC: 220AN: 154854Hom.: 3 AF XY: 0.000929 AC XY: 79AN XY: 85004
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GnomAD4 exome AF: 0.000684 AC: 961AN: 1405748Hom.: 11 Cov.: 33 AF XY: 0.000593 AC XY: 412AN XY: 694984
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GnomAD4 genome AF: 0.00642 AC: 978AN: 152238Hom.: 15 Cov.: 32 AF XY: 0.00583 AC XY: 434AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 14, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 17, 2023 | BS1, BS2, PS3 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2019 | This variant is associated with the following publications: (PMID: 24239320, 26377243, 3243553, 22069485, 20981092, 11500500, 24507774) - |
Familial type 3 hyperlipoproteinemia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1988 | - - |
Likely pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000041.2:c.487C>T in the APOE gene has an allele frequency of 0.021 in African subpopulation in the gnomAD database. The p.Arg163Cys (NM_000041.2:c.487C>T) variant has been reported to be associated with type III hyperlipoproteinemia (PMID: 25502880; 26802169). In vitro functional studies suggest that the p.Arg163Cys variant may affect protein function (PMID: 26802169). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PP3. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 15, 2021 | - - |
Benign, criteria provided, single submitter | research | H3Africa Consortium | Oct 28, 2020 | While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.069, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. - |
APOE-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at