Genetic Variant NM_000040.3:c.179+62T>C (chr11-116830958-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000040.3(APOC3):c.179+62T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000018 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APOC3
NM_000040.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.17

Publications

17 publications found

Variant links:

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

APOC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC3	NM_000040.3 link	c.179+62T>C		intron_variant	Intron 3 of 3	ENST00000227667.8	NP_000031.1	P02656A3KPE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8 link	c.179+62T>C		intron_variant	Intron 3 of 3	1	NM_000040.3	ENSP00000227667.2		P02656

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111370

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000887

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000184

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1237898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

617018

African (AFR)

AF:

0.00

AC:

AN:

26910

American (AMR)

AF:

0.00

AC:

AN:

39254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21032

East Asian (EAS)

AF:

0.00

AC:

AN:

31896

South Asian (SAS)

AF:

0.00

AC:

AN:

80472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3906

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

948356

Other (OTH)

AF:

0.00

AC:

AN:

49410

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

53972

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26426

American (AMR)

AF:

0.0000885

AC:

AN:

11302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2848

East Asian (EAS)

AF:

0.00

AC:

AN:

3974

South Asian (SAS)

AF:

0.00

AC:

AN:

3588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.0000184

AC:

AN:

54266

Other (OTH)

AF:

0.00

AC:

AN:

1546

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.24

(source)

DANN

Benign

0.76

PhyloP100

-2.2

PromoterAI

0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over