rs12720761

Variant names:

• chr2-21043733-T-C
• rs12720761
• NM_000384.3:c.82+131A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000384.3(APOB):​c.82+131A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,512,598 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.016 (74 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (63 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.622
• Publications: 3 publications found

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]

APOB Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000299295 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.82+131A>G		intron_variant	Intron 1 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.82+131A>G		intron_variant	Intron 1 of 28	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2451 AN: 151916 Hom.: 73 Cov.: 31

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00176 AC: 2398 AN: 1360570 Hom.: 63 AF XY: 0.00154 AC XY: 1030 AN XY: 670198

African (AFR) AF: 0.0620 AC: 1923 AN: 31036

American (AMR) AF: 0.00288 AC: 101 AN: 35026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23504

East Asian (EAS) AF: 0.00 AC: 0 AN: 35548

South Asian (SAS) AF: 0.000107 AC: 8 AN: 74944

European-Finnish (FIN) AF: 0.0000760 AC: 3 AN: 39476

Middle Eastern (MID) AF: 0.00436 AC: 24 AN: 5506

European-Non Finnish (NFE) AF: 0.0000897 AC: 95 AN: 1058686

Other (OTH) AF: 0.00429 AC: 244 AN: 56844

GnomAD4 genome AF: 0.0163 AC: 2471 AN: 152028 Hom.: 74 Cov.: 31 AF XY: 0.0157 AC XY: 1167 AN XY: 74344

African (AFR) AF: 0.0563 AC: 2336 AN: 41480

American (AMR) AF: 0.00609 AC: 93 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67968

Other (OTH) AF: 0.0114 AC: 24 AN: 2108

Alfa AF: 0.0153 Hom.: 6

Bravo AF: 0.0192

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.60
PhyloP100		-0.62
PromoterAI		0.043	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs12720761; hg19: chr2-21266605;