11-116830637-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_000040.3(APOC3):c.55C>T(p.Arg19Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,613,898 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (13 hom.)
• Consequence: APOC3 NM_000040.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0001268
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:3
• Conservation: PhyloP100: -0.649

Genes affected

APOC3 (HGNC:610): (apolipoprotein C3) This gene encodes a protein component of triglyceride (TG)-rich lipoproteins (TRLs) including very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. The encoded protein plays a role in role in the metabolism of these TRLs through multiple modes. This protein has been shown to promote the secretion of VLDL1, inhibit lipoprotein lipase enzyme activity, and delay catabolism of TRL remnants. Mutations in this gene are associated with low plasma triglyceride levels and reduced risk of ischemic cardiovascular disease, and hyperalphalipoproteinemia, which is characterized by elevated levels of high density lipoprotein (HDL) and HDL cholesterol in human patients. This gene and other related genes comprise an apolipoprotein gene cluster on chromosome 11. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOC3	NM_000040.3	c.55C>T	p.Arg19Ter	stop_gained, splice_region_variant	2/4	ENST00000227667.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOC3	ENST00000227667.8	c.55C>T	p.Arg19Ter	stop_gained, splice_region_variant	2/4	1	NM_000040.3	P1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251004 Hom.: 2 AF XY: 0.000817 AC XY: 111 AN XY: 135806

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000508 AC: 742 AN: 1461660 Hom.: 13 Cov.: 32 AF XY: 0.000587 AC XY: 427 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74440

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Apolipoprotein c-III deficiency Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	case-control	Falavarjan Branch, Islamic Azad University, , and Biochemistry Lab(Mahdieh Medical Diagnostic Center)	Mar 03, 2017	We interpret R19X as a pathogenic variant. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL cholesterol, and lower levels of LDL cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, which suggested that lifelong deficiency of apoC-III has a cardioprotective effect. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2015	Carriers of the R19X variant in the APOC3 gene have been reported to have increased high-densitylipoprotein levels and decreased triglyceride levels, as compared to non-carriers. In turn, it has beensuggested that this reduces the risk for heart disease (Crawford et al., 2014; Crosby et al., 2014; Jorgensenet al., 2014). This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. The R19X variant was not observed at any significantfrequency in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. We interpretR19X as a pathogenic variant. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 13, 2020

Variant summary: APOC3 c.55C>T (p.Arg19X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00066 in 251004 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOC3 causing Early Onset Coronary Artery Disease phenotype (2e-05), suggesting that the variant is not associated with Early Onset Coronary Artery Disease. In one case-control study, this variant was shown to have protective effect against Early Onset Coronary Artery Disease (Crosby_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -

Coronary heart disease Benign:1

protective, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 18, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	35
Dann	Uncertain	0.97
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.067	N
M_CAP	Uncertain	0.19	D
MutationTaster	Benign	1.0	A;A
Vest4		0.87, 0.85
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs76353203; hg19: chr11-116701353; COSMIC: COSV57139248;