rs72654430

Variant names:

• chr2-21001501-T-C
• rs72654430
• NM_000384.3:c.*229A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000384.3(APOB):​c.*229A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 511,510 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: APOB NM_000384.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.812
• Publications: 2 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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=-0.67).
• BP6: Variant 2-21001501-T-C is Benign according to our data. Variant chr2-21001501-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334057.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.*229A>G		3_prime_UTR	Exon 29 of 29	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.*229A>G		3_prime_UTR	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00106 AC: 382 AN: 359254 Hom.: 4 Cov.: 3 AF XY: 0.000982 AC XY: 186 AN XY: 189420

African (AFR) AF: 0.00176 AC: 17 AN: 9666

American (AMR) AF: 0.00436 AC: 49 AN: 11228

Ashkenazi Jewish (ASJ) AF: 0.00514 AC: 59 AN: 11480

East Asian (EAS) AF: 0.00 AC: 0 AN: 24478

South Asian (SAS) AF: 0.0000296 AC: 1 AN: 33746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22216

Middle Eastern (MID) AF: 0.00777 AC: 13 AN: 1674

European-Non Finnish (NFE) AF: 0.000841 AC: 188 AN: 223628

Other (OTH) AF: 0.00260 AC: 55 AN: 21138

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152256 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74444

African (AFR) AF: 0.00250 AC: 104 AN: 41552

American (AMR) AF: 0.00766 AC: 117 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68028

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00275

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypobetalipoproteinemia 1 (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.81
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: rs72654430; hg19: chr2-21224373;