NM_000384.3:c.25_27dupCTG

Variant names:

• chr2-21043918-C-CCAG
• rs1060500237
• NM_000384.3:c.25_27dupCTG

Variant summary

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

The NM_000384.3(APOB):​c.25_27dupCTG​(p.Leu9dup) variant causes a conservative 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 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

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 rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.25_27dupCTG	p.Leu9dup	conservative_inframe_insertion	Exon 1 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.25_27dupCTG	p.Leu9dup	conservative_inframe_insertion	Exon 1 of 29	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000399256.4	c.25_27dupCTG	p.Leu9dup	conservative_inframe_insertion	Exon 1 of 17	1		ENSP00000382200.4
APOB	ENST00000673739.2	n.25_27dupCTG		non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000501110.2
APOB	ENST00000673882.2	n.25_27dupCTG		non_coding_transcript_exon_variant	Exon 1 of 23			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000205 AC: 1 AN: 48892 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 29092

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 20 AN: 1259608 Hom.: 1 Cov.: 25 AF XY: 0.0000242 AC XY: 15 AN XY: 619254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000583

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

Asia WGS AF: 0.000292 AC: 1 AN: 3440

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

Mar 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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: rs1060500237; hg19: chr2-21266790;