rs147210663

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000040.3(APOC3):c.127G>A(p.Ala43Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000559 in 1,613,060 control chromosomes in the GnomAD database, including 4 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 0.0010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 4 hom. )

Consequence

APOC3
NM_000040.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 4.30

Variant links:

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]

APOC3 links:

APOC3 (HGNC:):

APOC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018726647).

BP6

Variant 11-116830844-G-A is Benign according to our data. Variant chr11-116830844-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139561.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr11-116830844-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 157 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC3	NM_000040.3 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	3/4	ENST00000227667.8	NP_000031.1	P02656A3KPE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	3/4	1	NM_000040.3	ENSP00000227667.2		P02656

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000868

AC:

217

AN:

250126

Hom.:

AF XY:

0.000716

AC XY:

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.00261

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000509

AC:

744

AN:

1460940

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

356

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152120

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000830

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	Reported in association with low plasma triglyceride levels (Liu et al., 2000; Crosby et al., 2014; Jorgensen et al., 2014; Bochem et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect on protein function (Sundaram et al., 2010); This variant is associated with the following publications: (PMID: 11060345, 20097930, 28825717, 24941082, 29237685, 32041611, 24941081, 31589614, 23701270) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	- -

Apolipoprotein c-III deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 03, 2014

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 01, 2023

- -

Coronary heart disease

Benign:1

protective, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 18, 2014

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;D;.;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

T;T;.;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Uncertain

0.53

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.3

D;D;D;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.021

D;D;D;.

Sift4G

Uncertain

0.033

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.34, 0.34

MVP

0.91

MPC

0.46

ClinPred

0.034

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over