rs12720761

Positions:

• chr2-21043733-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.82+131A>G		intron_variant		ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.82+131A>G		intron_variant		1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.82+131A>G		intron_variant		1		ENSP00000382200
APOB	ENST00000673739.2	c.82+131A>G		intron_variant, NMD_transcript_variant				ENSP00000501110
APOB	ENST00000673882.2	c.82+131A>G		intron_variant, NMD_transcript_variant				ENSP00000501253

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

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.0000760

Gnomad4 NFE exome AF: 0.0000897

Gnomad4 OTH exome AF: 0.00429

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

Gnomad4 AFR AF: 0.0563

Gnomad4 AMR AF: 0.00609

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0131 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

Uncertain significance, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

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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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12720761; hg19: chr2-21266605;