rs618354

Variant names:

• chr11-116830061-G-C
• rs618354
• NM_000040.3:c.-14+121G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000040.3(APOC3):​c.-14+121G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 185,628 control chromosomes in the GnomAD database, including 7,787 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6884 hom., cov: 32)
  • Exomes 𝑓: 0.21 (903 hom.)
• Consequence: APOC3 NM_000040.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000040.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC3	NM_000040.3	MANE Select	c.-14+121G>C		intron	N/A	NP_000031.1	A3KPE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC3	ENST00000227667.8	TSL:1 MANE Select	c.-14+121G>C		intron	N/A	ENSP00000227667.2	P02656
	APOC3	ENST00000863789.1		c.-285G>C		5_prime_UTR	Exon 1 of 4	ENSP00000533848.1
	APOC3	ENST00000863798.1		c.-299G>C		5_prime_UTR	Exon 1 of 4	ENSP00000533857.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42591 AN: 151790 Hom.: 6886 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.207 AC: 6975 AN: 33720 Hom.: 903 AF XY: 0.205 AC XY: 3546 AN XY: 17286

African (AFR) AF: 0.393 AC: 402 AN: 1022

American (AMR) AF: 0.161 AC: 499 AN: 3098

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 208 AN: 868

East Asian (EAS) AF: 0.0497 AC: 105 AN: 2112

South Asian (SAS) AF: 0.163 AC: 422 AN: 2586

European-Finnish (FIN) AF: 0.150 AC: 158 AN: 1054

Middle Eastern (MID) AF: 0.258 AC: 34 AN: 132

European-Non Finnish (NFE) AF: 0.226 AC: 4738 AN: 21010

Other (OTH) AF: 0.223 AC: 409 AN: 1838

GnomAD4 genome AF: 0.280 AC: 42610 AN: 151908 Hom.: 6884 Cov.: 32 AF XY: 0.274 AC XY: 20319 AN XY: 74286

African (AFR) AF: 0.438 AC: 18151 AN: 41394

American (AMR) AF: 0.195 AC: 2976 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3464

East Asian (EAS) AF: 0.0603 AC: 309 AN: 5124

South Asian (SAS) AF: 0.154 AC: 742 AN: 4820

European-Finnish (FIN) AF: 0.160 AC: 1692 AN: 10590

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16945 AN: 67928

Other (OTH) AF: 0.262 AC: 552 AN: 2110

Alfa AF: 0.270 Hom.: 721

Bravo AF: 0.290

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.44
PhyloP100		0.33
PromoterAI		-0.0090	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs618354; hg19: chr11-116700777;