11-116830844-G-T

Variant names:

• chr11-116830844-G-T
• rs147210663
• NM_000040.3:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000040.3(APOC3):​c.127G>T​(p.Ala43Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A43T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APOC3 NM_000040.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 54 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: Uncertain_significance. The variant received 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

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.127G>T	p.Ala43Ser	missense	Exon 3 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.127G>T	p.Ala43Ser	missense	Exon 3 of 4	ENSP00000227667.2
	APOC3	ENST00000630701.1	TSL:1	c.181G>T	p.Ala61Ser	missense	Exon 2 of 3	ENSP00000486182.1
	APOC3	ENST00000375345.3	TSL:5	c.181G>T	p.Ala61Ser	missense	Exon 3 of 4	ENSP00000364494.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250126 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460940 Hom.: 0 Cov.: 42 AF XY: 0.00000413 AC XY: 3 AN XY: 726766

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.47	D
PhyloP100		4.3
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.57		Gain of disorder (P = 0.0711)
MVP		0.91
MPC		0.45
ClinPred		0.92	D
GERP RS		4.8
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.61
Mutation Taster		=70/30	polymorphism

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: rs147210663; hg19: chr11-116701560;