rs138326449

Variant names:

• chr11-116830638-G-A
• rs138326449
• NM_000040.3:c.55+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-116830638-G-A
• chr11-116830638-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000040.3(APOC3):​c.55+1G>A variant causes a splice donor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:4
• Conservation: PhyloP100: 3.06
• Publications: 58 publications found

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 Gene-Disease associations (from GenCC):

• cholesterol-ester transfer protein deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC3	NM_000040.3	c.55+1G>A		splice_donor_variant, intron_variant	Intron 2 of 3	ENST00000227667.8	NP_000031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8	c.55+1G>A		splice_donor_variant, intron_variant	Intron 2 of 3	1	NM_000040.3	ENSP00000227667.2

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

GnomAD2 exomes AF: 0.00141 AC: 353 AN: 250966 AF XY: 0.00144

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 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

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86248

European-Finnish (FIN) AF: 0.00113 AC: 60 AN: 53186

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00233 AC: 2589 AN: 1111994

Other (OTH) AF: 0.00192 AC: 116 AN: 60396

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

African (AFR) AF: 0.000866 AC: 36 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 67968

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00208 Hom.: 1

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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Apolipoprotein c-III deficiency Pathogenic:2 Uncertain:1

May 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 03, 2014

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

-

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

not provided Uncertain:1 Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with increased plasma HDL cholesterol levels and reduced triglyceride levels which may confer a reduction in the risk for heart disease (PMID: 23685560, 23701270, 24941082, 25225788, 24941081, 28008009, 27114411, 27146844, 30255797, 34834584, 35460704, 36325899); Identified in a woman with HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet) in published literature (PMID: 33059327); 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, 30405126, 30255797, 27146844, 29348120, 31589614, 34426522, 34662886, 31345219, 24941081, 32041611, 28787443, 23685560, 34834584, 33059327, 36325899, 35460704, 36220816) -

not specified Benign:1

Jul 24, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 18, 2014

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Benign:1

Apr 02, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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
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
PhyloP100		3.1
GERP RS		4.9
PromoterAI		-0.065	Neutral
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

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