11-116830638-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_000040.3(APOC3):c.55+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,613,856 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: APOC3 NM_000040.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:3
• Conservation: PhyloP100: 3.06

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 Likely_benign. Variant got -2 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.221
• BS2: High AC in GnomAd at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOC3	NM_000040.3	c.55+1G>A		splice_donor_variant		ENST00000227667.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOC3	ENST00000227667.8	c.55+1G>A		splice_donor_variant		1	NM_000040.3	P1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00141 AC: 353 AN: 250966 Hom.: 0 AF XY: 0.00144 AC XY: 195 AN XY: 135788

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00199 AC: 2912 AN: 1461622 Hom.: 4 Cov.: 32 AF XY: 0.00201 AC XY: 1462 AN XY: 727128

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74442

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00151

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Apolipoprotein c-III deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	This APOC3 splicing variant NM_000040.3:c.55+1G>A (rs138326449) was described for the first time in PMID: 23701270 and has been associated with decreased plasma triglyceride and apoC-III levels. Normally it has been reported to show an atheroprotective effect (see also PMID: 24941081; PMID: 24941081; PMID: 25225788; PMID: 25962519; PMID: 27114411; PMID: 30255797; PMID: 32041611; PMID: 34548093). We report this variant in a 57-year-old male patient with combined hypolipidaemia, who presented with premature peripheral vascular disease, and also in one of his two sons, 32-years-old. Both individuals manifested decreased TG levels (between the 10th and 25th centiles). The atheroprotective effect has not been seen in the patients, most likely because they also carried a novel ABCA1 variant NM_005502.4:c.1857_1858delinsAT, possibly responsible for their decreased HDL levels (see PMID: 36876364). The effect of the APOC3 splicing variant on TG levels is further confirmed by the evidence, that the second son, 32-years-old, who carried the ABCA1 variant but not the APOC3 variant, had TG values between 75th and 90th centiles. This variant is listed as a disease-causing in the HGMD database (CS138510) and GnomAD Exomes Version: 4.0 indicates the frequency of ƒ = 0.00199. -
Pathogenic, flagged submission	literature only	OMIM	Jul 03, 2014	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	Canonical splice site variant; heterozygous loss-of-function variants in the APOC3 gene have been reported in association with hypotriglyceridemia and protection against cardiovascular disease; This variant is associated with the following publications: (PMID: 23701270, 25225788, 24941082, 28008009, 27114411, 24941081, 30405126, 30255797, 27146844, 29348120, 31589614, 34426522, 32041611, 28787443, 23685560, 34834584) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 06, 2023	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

The c.55+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the APOC3 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 24, 2023

Variant summary: APOC3 c.55+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 250966 control chromosomes (gnomAD). The observed variant frequency is approximately 70-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. c.55+1G>A has been reported in the literature in association with reduced levels of triglycerides and increased levels of HDL in heterozygous individuals and was shown to result in an atheroprotective lipid profile with lowered risk of coronary heart disease (Bochem_2014, Crosby_2014, Jorgensen_2014, Timpson_2014, Goyal_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23701270, 30255797, 24941081, 27114411, 32041611, 34548093, 24941082, 25225788). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=1). 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	Pathogenic	0.17
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138326449; hg19: chr11-116701354; COSMIC: COSV57138265;