rs5128

Positions:

• chr11-116832924-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000040.3(APOC3):​c.*40G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,612,872 control chromosomes in the GnomAD database, including 630,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56779 hom., cov: 33)
  • Exomes 𝑓: 0.88 (573988 hom.)
• Consequence: APOC3 NM_000040.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -2.16

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-116832924-G-C is Benign according to our data. Variant chr11-116832924-G-C is described in ClinVar as [Benign]. Clinvar id is 1250845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-116832924-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC3	NM_000040.3	c.*40G>C		3_prime_UTR_variant	4/4	ENST00000227667.8	NP_000031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8	c.*40G>C		3_prime_UTR_variant	4/4	1	NM_000040.3	ENSP00000227667.2
APOC3	ENST00000630701.1	c.*40G>C		3_prime_UTR_variant	3/3	1		ENSP00000486182.1
APOC3	ENST00000375345.3	c.*40G>C		3_prime_UTR_variant	4/4	5		ENSP00000364494.1

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131089 AN: 152120 Hom.: 56755 Cov.: 33

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.947

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.858

GnomAD3 exomes AF: 0.839 AC: 210515 AN: 250898 Hom.: 89243 AF XY: 0.836 AC XY: 113526 AN XY: 135734

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.787

Gnomad ASJ exome AF: 0.860

Gnomad EAS exome AF: 0.697

Gnomad SAS exome AF: 0.697

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.884 AC: 1290860 AN: 1460634 Hom.: 573988 Cov.: 48 AF XY: 0.878 AC XY: 638016 AN XY: 726638

Gnomad4 AFR exome AF: 0.843

Gnomad4 AMR exome AF: 0.791

Gnomad4 ASJ exome AF: 0.861

Gnomad4 EAS exome AF: 0.671

Gnomad4 SAS exome AF: 0.698

Gnomad4 FIN exome AF: 0.873

Gnomad4 NFE exome AF: 0.913

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.862 AC: 131167 AN: 152238 Hom.: 56779 Cov.: 33 AF XY: 0.854 AC XY: 63577 AN XY: 74436

Gnomad4 AFR AF: 0.848

Gnomad4 AMR AF: 0.805

Gnomad4 ASJ AF: 0.858

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.867

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.853

Alfa AF: 0.882 Hom.: 10905

Bravo AF: 0.863

Asia WGS AF: 0.687 AC: 2394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 27624799, 15100713, 19034316) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myocardial infarction, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

reference population

iDNA Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.98
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs5128; hg19: chr11-116703640; COSMIC: COSV52636718; COSMIC: COSV52636718;