rs4225

chr11-116832955-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000040.3(APOC3):c.*71G>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 0.566 in 1,606,286 control chromosomes in the GnomAD database, including 274,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (18615 hom., cov: 33)
  • Exomes 𝑓: 0.58 (256337 hom.)
• Consequence: APOC3 NM_000040.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.142

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-116832955-G-T is Benign according to our data. Variant chr11-116832955-G-T is described in ClinVar as [Benign]. Clinvar id is 1225805.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-116832955-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOC3	NM_000040.3	c.*71G>T		3_prime_UTR_variant	4/4	ENST00000227667.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOC3	ENST00000227667.8	c.*71G>T		3_prime_UTR_variant	4/4	1	NM_000040.3	P1
APOC3	ENST00000630701.1	c.*71G>T		3_prime_UTR_variant	3/3	1
APOC3	ENST00000375345.3	c.*71G>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68199 AN: 151968 Hom.: 18618 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.477

GnomAD4 exome AF: 0.579 AC: 841593 AN: 1454200 Hom.: 256337 Cov.: 30 AF XY: 0.572 AC XY: 414102 AN XY: 723704

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.540

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.638

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.448 AC: 68184 AN: 152086 Hom.: 18615 Cov.: 33 AF XY: 0.440 AC XY: 32704 AN XY: 74326

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.627

Gnomad4 OTH AF: 0.471

Alfa AF: 0.479 Hom.: 2945

Bravo AF: 0.433

Asia WGS AF: 0.215 AC: 752 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

This variant is associated with the following publications: (PMID: 30420299, 30782561, 27624799) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.2
Dann	Benign	0.76
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: rs4225; hg19: chr11-116703671; COSMIC: COSV52635690; COSMIC: COSV52635690;