rs199768005
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2
The NM_000041.4(APOE):c.761T>A(p.Val254Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,562,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00066 ( 2 hom. )
Consequence
APOE
NM_000041.4 missense
NM_000041.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 0.0590
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 -7 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 8 benign (71%) in NM_000041.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.034093946).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000473 (72/152198) while in subpopulation NFE AF= 0.000765 (52/67976). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOE | NM_000041.4 | c.761T>A | p.Val254Glu | missense_variant | 4/4 | ENST00000252486.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOE | ENST00000252486.9 | c.761T>A | p.Val254Glu | missense_variant | 4/4 | 1 | NM_000041.4 | P1 | |
APOE | ENST00000434152.5 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000473 AC: 72AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000452 AC: 75AN: 165832Hom.: 1 AF XY: 0.000494 AC XY: 45AN XY: 91184
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GnomAD4 exome AF: 0.000659 AC: 929AN: 1410160Hom.: 2 Cov.: 33 AF XY: 0.000643 AC XY: 449AN XY: 698452
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GnomAD4 genome ? AF: 0.000473 AC: 72AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74426
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as APOE3-Jacksonville, APOE3-Jac, and p.(V236E); Has not been previously published in association with dyslipidemia to our knowledge; This variant is associated with the following publications: (PMID: 25560647, 32808727, 34058468, 24607147, 34586832) - |
Familial type 3 hyperlipoproteinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1993 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
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