rs147210663

chr11-116830844-G-Achr11-116830844-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 4.30

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 -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: {Uncertain_significance=1, Benign=2, Likely_benign=1}. Variant chr11-116830844-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOC3	NM_000040.3	c.127G>A	p.Ala43Thr	missense_variant	3/4	ENST00000227667.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOC3	ENST00000227667.8	c.127G>A	p.Ala43Thr	missense_variant	3/4	1	NM_000040.3	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152002 Hom.: 0 Cov.: 31

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.: 1 AF XY: 0.000716 AC XY: 97 AN XY: 135568

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.: 4 Cov.: 42 AF XY: 0.000490 AC XY: 356 AN XY: 726766

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.: 0 Cov.: 31 AF XY: 0.000995 AC XY: 74 AN XY: 74362

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.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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	Invitae	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	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;.;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs147210663; hg19: chr11-116701560; COSMIC: COSV52637070; COSMIC: COSV52637070;