rs673548

Variant names:

• chr2-21014672-G-A
• rs673548
• NM_000384.3:c.3697-79C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21014672-G-A
• chr2-21014672-G-T

Variant summary

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

The NM_000384.3(APOB):​c.3697-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,430,782 control chromosomes in the GnomAD database, including 53,513 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 0.25 (5628 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47885 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.678
• Publications: 92 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.3697-79C>T		intron_variant	Intron 23 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.3697-79C>T		intron_variant	Intron 23 of 28	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000673739.2	n.*3003-79C>T		intron_variant	Intron 22 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.*2792-79C>T		intron_variant	Intron 21 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37936 AN: 151978 Hom.: 5628 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.247 AC: 315505 AN: 1278686 Hom.: 47885 AF XY: 0.254 AC XY: 163961 AN XY: 644286

African (AFR) AF: 0.214 AC: 6265 AN: 29324

American (AMR) AF: 0.257 AC: 10460 AN: 40762

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 4712 AN: 24396

East Asian (EAS) AF: 0.726 AC: 28092 AN: 38684

South Asian (SAS) AF: 0.496 AC: 39207 AN: 79124

European-Finnish (FIN) AF: 0.266 AC: 13976 AN: 52538

Middle Eastern (MID) AF: 0.319 AC: 1698 AN: 5320

European-Non Finnish (NFE) AF: 0.206 AC: 196847 AN: 954532

Other (OTH) AF: 0.264 AC: 14248 AN: 54006

GnomAD4 genome AF: 0.249 AC: 37944 AN: 152096 Hom.: 5628 Cov.: 33 AF XY: 0.258 AC XY: 19161 AN XY: 74332

African (AFR) AF: 0.219 AC: 9070 AN: 41494

American (AMR) AF: 0.236 AC: 3601 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3472

East Asian (EAS) AF: 0.728 AC: 3768 AN: 5174

South Asian (SAS) AF: 0.527 AC: 2540 AN: 4820

European-Finnish (FIN) AF: 0.263 AC: 2771 AN: 10546

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14725 AN: 67994

Other (OTH) AF: 0.246 AC: 518 AN: 2108

Alfa AF: 0.234 Hom.: 21105

Bravo AF: 0.244

Asia WGS AF: 0.600 AC: 2082 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.86
DANN	Benign	0.67
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs673548; hg19: chr2-21237544;