NM_000040.3:c.*40G>C

Variant names:

• chr11-116832924-G-C
• rs5128
• NM_000040.3:c.*40G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000040.3(APOC3):​c.*40G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,612,872 control chromosomes in the GnomAD database, including 630,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56779 hom., cov: 33)
  • Exomes 𝑓: 0.88 (573988 hom.)
• Consequence: APOC3 NM_000040.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -2.16
• Publications: 191 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-116832924-G-C is Benign according to our data. Variant chr11-116832924-G-C is described in ClinVar as Benign. ClinVar VariationId is 1250845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.901 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.*40G>C		3_prime_UTR	Exon 4 of 4	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.*40G>C		3_prime_UTR	Exon 4 of 4	ENSP00000227667.2	P02656
	APOC3	ENST00000630701.1	TSL:1	c.*40G>C		3_prime_UTR	Exon 3 of 3	ENSP00000486182.1	B0YIW2
	APOC3	ENST00000863804.1		c.*40G>C		3_prime_UTR	Exon 4 of 4	ENSP00000533863.1

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131089 AN: 152120 Hom.: 56755 Cov.: 33

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.947

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.858

GnomAD2 exomes AF: 0.839 AC: 210515 AN: 250898 AF XY: 0.836

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.787

Gnomad ASJ exome AF: 0.860

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.884 AC: 1290860 AN: 1460634 Hom.: 573988 Cov.: 48 AF XY: 0.878 AC XY: 638016 AN XY: 726638

African (AFR) AF: 0.843 AC: 28219 AN: 33464

American (AMR) AF: 0.791 AC: 35346 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 22488 AN: 26130

East Asian (EAS) AF: 0.671 AC: 26638 AN: 39686

South Asian (SAS) AF: 0.698 AC: 60206 AN: 86218

European-Finnish (FIN) AF: 0.873 AC: 46045 AN: 52760

Middle Eastern (MID) AF: 0.845 AC: 4660 AN: 5512

European-Non Finnish (NFE) AF: 0.913 AC: 1014785 AN: 1111832

Other (OTH) AF: 0.870 AC: 52473 AN: 60334

GnomAD4 genome AF: 0.862 AC: 131167 AN: 152238 Hom.: 56779 Cov.: 33 AF XY: 0.854 AC XY: 63577 AN XY: 74436

African (AFR) AF: 0.848 AC: 35227 AN: 41526

American (AMR) AF: 0.805 AC: 12324 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2978 AN: 3470

East Asian (EAS) AF: 0.686 AC: 3548 AN: 5172

South Asian (SAS) AF: 0.683 AC: 3297 AN: 4826

European-Finnish (FIN) AF: 0.867 AC: 9196 AN: 10602

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61678 AN: 68016

Other (OTH) AF: 0.853 AC: 1806 AN: 2116

Alfa AF: 0.882 Hom.: 10905

Bravo AF: 0.863

Asia WGS AF: 0.687 AC: 2394 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Myocardial infarction, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.98
DANN	Benign	0.72
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5128; hg19: chr11-116703640; COSMIC: COSV52636718; COSMIC: COSV52636718;