rs1060500237
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000384.3(APOB):c.27_28insCTG(p.Leu9dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,411,560 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 1 hom. )
Consequence
APOB
NM_000384.3 inframe_insertion
NM_000384.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.152
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.27_28insCTG | p.Leu9dup | inframe_insertion | 1/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.27_28insCTG | p.Leu9dup | inframe_insertion | 1/29 | 1 | NM_000384.3 | P1 | |
APOB | ENST00000399256.4 | c.27_28insCTG | p.Leu9dup | inframe_insertion | 1/17 | 1 | |||
APOB | ENST00000673739.2 | c.27_28insCTG | p.Leu9dup | inframe_insertion, NMD_transcript_variant | 1/25 | ||||
APOB | ENST00000673882.2 | c.27_28insCTG | p.Leu9dup | inframe_insertion, NMD_transcript_variant | 1/23 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151844Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000205 AC: 1AN: 48892Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 29092
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GnomAD4 exome AF: 0.0000159 AC: 20AN: 1259608Hom.: 1 Cov.: 25 AF XY: 0.0000242 AC XY: 15AN XY: 619254
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | This variant, c.25_27dup, results in the insertion of 1 amino acid(s) of the APOB protein (p.Leu9dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with APOB-related conditions. ClinVar contains an entry for this variant (Variation ID: 404405). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.25_27dupCTG variant (also known as p.L9dup), located in coding exon 1 of the APOB gene, results from an in-frame duplication of CTG at nucleotide positions 25 to 27. This results in the duplication of an extra leucine residue between codons 9 and 10. This amino acid position is conserved on limited sequence alignment. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at