chr2-21002402-A-C

Variant names:

• chr2-21002402-A-C
• rs141339310
• NM_000384.3:c.13020T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000384.3(APOB):​c.13020T>G​(p.Tyr4340*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y4340Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: APOB NM_000384.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.790
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-21002402-A-C is Pathogenic according to our data. Variant chr2-21002402-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1330071.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.13020T>G	p.Tyr4340*	stop_gained	Exon 29 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.13020T>G	p.Tyr4340*	stop_gained	Exon 29 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450184 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720842

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32864

American (AMR) AF: 0.00 AC: 0 AN: 43418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105576

Other (OTH) AF: 0.00 AC: 0 AN: 59854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Jan 27, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is predicted to cause the premature termination of APOB protein synthesis. To the best of our knowledge, the variant has not been reported in online databases or the published literature. This variant has not been reported in large, multi-ethnic general populations. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Based on the available information, the variant is predicted to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Benign	0.89
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.17	N
PhyloP100		-0.79
Vest4		0.71
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=27/173	disease causing

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: rs141339310; hg19: chr2-21225274;