rs878853971

Positions:

• chr2-21043898-CGCAGGCAGCGCCA-CAGCGCAG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000384.3(APOB):​c.35_47delinsCTGCGCT​(p.Leu12_Ala16delinsProAlaLeu) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: APOB NM_000384.3 protein_altering
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.29

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]

ACMG classification

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	Protein	UniProt
APOB	NM_000384.3	c.35_47delinsCTGCGCT	p.Leu12_Ala16delinsProAlaLeu	protein_altering_variant	1/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.35_47delinsCTGCGCT	p.Leu12_Ala16delinsProAlaLeu	protein_altering_variant	1/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.35_47delinsCTGCGCT	p.Leu12_Ala16delinsProAlaLeu	protein_altering_variant	1/17	1		ENSP00000382200
APOB	ENST00000673739.2	c.35_47delinsCTGCGCT	p.Leu12_Ala16delinsProAlaLeu	protein_altering_variant, NMD_transcript_variant	1/25			ENSP00000501110
APOB	ENST00000673882.2	c.35_47delinsCTGCGCT	p.Leu12_Ala16delinsProAlaLeu	protein_altering_variant, NMD_transcript_variant	1/23			ENSP00000501253

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2019

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. Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with APOB-related conditions. ClinVar contains an entry for this variant (Variation ID: 237745). This variant is not present in population databases (ExAC no frequency). This variant, c.35_47delinsCTGCGCT, is a complex sequence change that results in the deletion of 5 amino acids and insertion of 3 amino acids in the APOB protein (p.Leu12_Ala16delinsProAlaLeu). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2023

The c.35_47del13insCTGCGCT variant (also known as p.L12_A16delinsPAL), located in coding exon 1 of the APOB gene, results from an in-frame deletion of TGGCGCTGCCTGC and insertion of CTGCGCT at nucleotide positions 35 to 47. This results in the in-frame deletion five residues (LALPA) and insertion of 3 residues (PAL) between codons 12 and 16. This amino acid region is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853971; hg19: chr2-21266771;