2-21001939-ACTG-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000384.3(APOB):c.13480_13482del(p.Gln4494del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 1 hom. )
Consequence
APOB
NM_000384.3 inframe_deletion
NM_000384.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.04
Genes affected
APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000384.3. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.13480_13482del | p.Gln4494del | inframe_deletion | 29/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.13480_13482del | p.Gln4494del | inframe_deletion | 29/29 | 1 | NM_000384.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000217 AC: 33AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000384 AC: 96AN: 250322Hom.: 0 AF XY: 0.000391 AC XY: 53AN XY: 135440
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GnomAD4 exome AF: 0.000380 AC: 555AN: 1461758Hom.: 1 AF XY: 0.000338 AC XY: 246AN XY: 727184
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GnomAD4 genome AF: 0.000217 AC: 33AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/192 non-FH alleles - |
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Hypercholesterolemia, autosomal dominant, type B Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2023 | In the published literature, this variant has been reported in individuals affected with hypercholesterolemia (PMIDs: 31980526 (2020), 32770674 (2020), 33269076 (2021), 33303402 (2021), 33418990 (2021), and 35913489 (2022)), and did not fully co-segregate in one family (PMID: 24234650 (2014)). Additionally, functional studies have shown this variant caused impaired LDL binding and uptake (PMIDs: 24234650 (2014) and 26643808 (2015)). The frequency of this variant in the general population, 0.0007 (90/128394 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2022 | Published functional studies demonstrate a damaging effect through a 40% decrease in internalization in lymphocytes and HepG2 cells (Alves et al., 2014); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26643808, 24234650, 32719484, 32770674, 33269076, 33418990, 33303402, 35913489, 31980526) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2022 | This alteration is classified as likely 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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at