11-116830844-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOC3	NM_000040.3	c.127G>T	p.Ala43Ser	missense_variant	3/4	ENST00000227667.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOC3	ENST00000227667.8	c.127G>T	p.Ala43Ser	missense_variant	3/4	1	NM_000040.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250126 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135568

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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 v4.3

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
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T;.;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	0.83	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.022	D;D;D;.
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.32, 0.31
MutPred		0.57		Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);.;.;
MVP		0.91
MPC		0.45
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs147210663; hg19: chr11-116701560;