rs3791981

Variant names:

• chr2-21022495-A-G
• rs3791981
• NM_000384.3:c.2816+336T>C

Variant summary

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

The NM_000384.3(APOB):​c.2816+336T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,132 control chromosomes in the GnomAD database, including 4,088 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (4088 hom., cov: 32)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 16 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.2816+336T>C		intron_variant	Intron 18 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.2816+336T>C		intron_variant	Intron 18 of 28	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000673739.2	n.*2122+336T>C		intron_variant	Intron 17 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.*2122+336T>C		intron_variant	Intron 17 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28874 AN: 152012 Hom.: 4068 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.0399

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.193

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

GnomAD4 genome AF: 0.190 AC: 28945 AN: 152132 Hom.: 4088 Cov.: 32 AF XY: 0.191 AC XY: 14216 AN XY: 74372

African (AFR) AF: 0.387 AC: 16050 AN: 41452

American (AMR) AF: 0.203 AC: 3103 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1057 AN: 3470

East Asian (EAS) AF: 0.0402 AC: 208 AN: 5176

South Asian (SAS) AF: 0.133 AC: 640 AN: 4810

European-Finnish (FIN) AF: 0.108 AC: 1148 AN: 10602

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6159 AN: 68018

Other (OTH) AF: 0.192 AC: 406 AN: 2112

Alfa AF: 0.231 Hom.: 2178

Bravo AF: 0.208

Asia WGS AF: 0.111 AC: 383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.38
DANN	Benign	0.54
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3791981; hg19: chr2-21245367;