rs12714224

Variant names:

• chr2-21032294-G-T
• rs12714224
• NM_000384.3:c.1352+60C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000384.3(APOB):​c.1352+60C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,439,188 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (30 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0350
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00779 (1187/152328) while in subpopulation AFR AF = 0.0161 (671/41572). AF 95% confidence interval is 0.0151. There are 9 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.1352+60C>A		intron	N/A	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.1352+60C>A		intron	N/A	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.1352+60C>A		intron	N/A	ENSP00000382200.4
	APOB	ENST00000673739.2		n.*658+60C>A		intron	N/A	ENSP00000501110.2

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1189 AN: 152210 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00355 AC: 4562 AN: 1286860 Hom.: 30 AF XY: 0.00365 AC XY: 2370 AN XY: 649324

African (AFR) AF: 0.0178 AC: 538 AN: 30226

American (AMR) AF: 0.00766 AC: 341 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 287 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.00133 AC: 110 AN: 82424

European-Finnish (FIN) AF: 0.0000929 AC: 4 AN: 43064

Middle Eastern (MID) AF: 0.0474 AC: 186 AN: 3928

European-Non Finnish (NFE) AF: 0.00279 AC: 2685 AN: 963654

Other (OTH) AF: 0.00748 AC: 411 AN: 54942

GnomAD4 genome AF: 0.00779 AC: 1187 AN: 152328 Hom.: 9 Cov.: 33 AF XY: 0.00788 AC XY: 587 AN XY: 74488

African (AFR) AF: 0.0161 AC: 671 AN: 41572

American (AMR) AF: 0.0118 AC: 180 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.00320 AC: 218 AN: 68028

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00465 Hom.: 0

Bravo AF: 0.00874

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hypercholesterolemia, familial, 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.77
DANN	Benign	0.67
PhyloP100		0.035
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs12714224; hg19: chr2-21255166;