chr11-116830637-C-G

Variant names:

• chr11-116830637-C-G
• rs76353203
• NM_000040.3:c.55C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_000040.3(APOC3):​c.55C>G​(p.Arg19Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APOC3 NM_000040.3 missense, splice_region
• Scores: Splicing: ADA: 0.00007906
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.649
• Publications: 112 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.057647 (below the threshold of 3.09). Trascript score misZ: 0.23808 (below the threshold of 3.09). GenCC associations: The gene is linked to cholesterol-ester transfer protein deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3226535).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC3	NM_000040.3	MANE Select	c.55C>G	p.Arg19Gly	missense splice_region	Exon 2 of 4	NP_000031.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC3	ENST00000227667.8	TSL:1 MANE Select	c.55C>G	p.Arg19Gly	missense splice_region	Exon 2 of 4	ENSP00000227667.2
	APOC3	ENST00000630701.1	TSL:1	c.109C>G	p.Arg37Gly	missense splice_region	Exon 1 of 3	ENSP00000486182.1
	APOC3	ENST00000375345.3	TSL:5	c.109C>G	p.Arg37Gly	missense splice_region	Exon 2 of 4	ENSP00000364494.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251004 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.65	T
PhyloP100		-0.65
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.024	D
Polyphen		0.031	B
Vest4		0.18
MutPred		0.70		Loss of stability (P = 0.0661)
MVP		0.84
MPC		0.11
ClinPred		0.18	T
GERP RS		-2.6
PromoterAI		0.089	Neutral
Varity_R		0.12
gMVP		0.17
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.21
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: rs76353203; hg19: chr11-116701353;