Genetic Variant NM_000040.3:c.-14+121G>C (chr11-116830061-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000040.3(APOC3):c.-14+121G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 185,628 control chromosomes in the GnomAD database, including 7,787 homozygotes. 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 0.28 ( 6884 hom., cov: 32)

Exomes 𝑓: 0.21 ( 903 hom. )

Consequence

APOC3
NM_000040.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.326

Publications

8 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC3	NM_000040.3 link	c.-14+121G>C		intron_variant	Intron 1 of 3	ENST00000227667.8	NP_000031.1	P02656A3KPE2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOC3	ENST00000227667.8 link	c.-14+121G>C	intron_variant	Intron 1 of 3	1	NM_000040.3	ENSP00000227667.2	P02656
APOC3	ENST00000375345.3 link	c.-37+121G>C	intron_variant	Intron 1 of 3	5		ENSP00000364494.1	B0YIW2
APOC3	ENST00000433777.5 link	c.-14+175G>C	intron_variant	Intron 1 of 2	5		ENSP00000410614.1	C9J2Q0
APOC3	ENST00000470144.1 link	n.19+121G>C	intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42591

AN:

151790

Hom.:

6886

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.0604

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.266

GnomAD4 exome

AF:

0.207

AC:

6975

AN:

33720

Hom.:

903

AF XY:

0.205

AC XY:

3546

AN XY:

17286

show subpopulations

African (AFR)

AF:

0.393

AC:

402

AN:

1022

American (AMR)

AF:

0.161

AC:

499

AN:

3098

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

208

AN:

868

East Asian (EAS)

AF:

0.0497

AC:

105

AN:

2112

South Asian (SAS)

AF:

0.163

AC:

422

AN:

2586

European-Finnish (FIN)

AF:

0.150

AC:

158

AN:

1054

Middle Eastern (MID)

AF:

0.258

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.226

AC:

4738

AN:

21010

Other (OTH)

AF:

0.223

AC:

409

AN:

1838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

248

495

743

990

1238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.280

AC:

42610

AN:

151908

Hom.:

6884

Cov.:

AF XY:

0.274

AC XY:

20319

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.438

AC:

18151

AN:

41394

American (AMR)

AF:

0.195

AC:

2976

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

916

AN:

3464

East Asian (EAS)

AF:

0.0603

AC:

309

AN:

5124

South Asian (SAS)

AF:

0.154

AC:

742

AN:

4820

European-Finnish (FIN)

AF:

0.160

AC:

1692

AN:

10590

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16945

AN:

67928

Other (OTH)

AF:

0.262

AC:

552

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1494

2988

4482

5976

7470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.270

Hom.:

721

Bravo

AF:

0.290

Asia WGS

AF:

0.120

AC:

415

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.3

(source)

DANN

Benign

0.44

PhyloP100

0.33

PromoterAI

-0.0090

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over