11-116830953-G-C

Variant names:

• chr11-116830953-G-C
• rs2070667
• NM_000040.3:c.179+57G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000040.3(APOC3):​c.179+57G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,181,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0013 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: APOC3 NM_000040.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182
• Publications: 15 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC3	NM_000040.3	c.179+57G>C		intron_variant	Intron 3 of 3	ENST00000227667.8	NP_000031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8	c.179+57G>C		intron_variant	Intron 3 of 3	1	NM_000040.3	ENSP00000227667.2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 144 AN: 111410 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000505

Gnomad ASJ AF: 0.000391

Gnomad EAS AF: 0.000540

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000512

Gnomad OTH AF: 0.00273

GnomAD4 exome AF: 0.00000934 AC: 10 AN: 1070166 Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 6 AN XY: 539004

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31056

American (AMR) AF: 0.00 AC: 0 AN: 39192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19154

East Asian (EAS) AF: 0.0000326 AC: 1 AN: 30628

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77894

European-Finnish (FIN) AF: 0.0000287 AC: 1 AN: 34894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3648

European-Non Finnish (NFE) AF: 0.00000887 AC: 7 AN: 789364

Other (OTH) AF: 0.00 AC: 0 AN: 44336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00129 AC: 144 AN: 111514 Hom.: 0 Cov.: 23 AF XY: 0.00154 AC XY: 82 AN XY: 53194

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00276 AC: 100 AN: 36194

American (AMR) AF: 0.000504 AC: 5 AN: 9916

Ashkenazi Jewish (ASJ) AF: 0.000391 AC: 1 AN: 2560

East Asian (EAS) AF: 0.000539 AC: 2 AN: 3708

South Asian (SAS) AF: 0.000622 AC: 2 AN: 3218

European-Finnish (FIN) AF: 0.00104 AC: 5 AN: 4824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.000512 AC: 25 AN: 48800

Other (OTH) AF: 0.00271 AC: 4 AN: 1478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.54
PhyloP100		0.18
PromoterAI		0.027	Neutral

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: rs2070667; hg19: chr11-116701669;