rs142151703

Variant names:

• chr2-21001551-G-A
• rs142151703
• NM_000384.3:c.*179C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21001551-G-A
• chr2-21001551-G-C

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.*179C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 603,896 control chromosomes in the GnomAD database, including 15 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 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (11 hom.)
• Consequence: APOB NM_000384.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.15
• 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=-0.81).
• BP6: Variant 2-21001551-G-A is Benign according to our data. Variant chr2-21001551-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334060.
• BS2: High Homozygotes in GnomAd4 at 4 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.*179C>T		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.*179C>T		3_prime_UTR	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 562 AN: 151974 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.00477 AC: 2155 AN: 451804 Hom.: 11 Cov.: 5 AF XY: 0.00461 AC XY: 1097 AN XY: 237854

African (AFR) AF: 0.00101 AC: 12 AN: 11842

American (AMR) AF: 0.00290 AC: 43 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.00829 AC: 111 AN: 13386

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29638

South Asian (SAS) AF: 0.00355 AC: 147 AN: 41374

European-Finnish (FIN) AF: 0.0146 AC: 438 AN: 30014

Middle Eastern (MID) AF: 0.00907 AC: 18 AN: 1984

European-Non Finnish (NFE) AF: 0.00444 AC: 1257 AN: 283084

Other (OTH) AF: 0.00499 AC: 128 AN: 25666

GnomAD4 genome AF: 0.00370 AC: 562 AN: 152092 Hom.: 4 Cov.: 32 AF XY: 0.00424 AC XY: 315 AN XY: 74348

African (AFR) AF: 0.000603 AC: 25 AN: 41454

American (AMR) AF: 0.00301 AC: 46 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4814

European-Finnish (FIN) AF: 0.0156 AC: 165 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68020

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.60
PhyloP100		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: rs142151703; hg19: chr2-21224423;