19-44908783-C-T
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
Consequence
NM_000041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
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
GnomAD3 exomes AF: 0.00142 AC: 220AN: 154854Hom.: 3 AF XY: 0.000929 AC XY: 79AN XY: 85004
GnomAD4 exome AF: 0.000684 AC: 961AN: 1405748Hom.: 11 Cov.: 33 AF XY: 0.000593 AC XY: 412AN XY: 694984
GnomAD4 genome AF: 0.00642 AC: 978AN: 152238Hom.: 15 Cov.: 32 AF XY: 0.00583 AC XY: 434AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
This variant is associated with the following publications: (PMID: 24239320, 26377243, 3243553, 22069485, 20981092, 11500500, 24507774) -
BS1, BS2, PS3 -
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Familial type 3 hyperlipoproteinemia Pathogenic:2
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. -
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not specified Benign:2
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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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at