Genetic Variant APOC4:p.Gly52Asp (chr19-44944827-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001646.3(APOC4):c.155G>A(p.Gly52Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,608,914 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0047 ( 53 hom. )

Consequence

APOC4
NM_001646.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.419

Publications

12 publications found

Variant links:

Genes affected

APOC4 (HGNC:611): (apolipoprotein C4) This gene encodes a lipid-binding protein belonging to the apolipoprotein gene family. The protein is thought to play a role in lipid metabolism. Polymorphisms in this gene may influence circulating lipid levels and may be associated with coronary artery disease risk. This gene is present in a cluster with other related apolipoprotein genes on chromosome 19. Naturally occurring read-through transcription exists between this gene and the neighboring downstream apolipoprotein C-II (APOC2) gene. [provided by RefSeq, Mar 2011]

APOC4 links:

APOC4-APOC2 (HGNC:44426): (APOC4-APOC2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring apolipoprotein C-IV (APOC4) and apolipoprotein C-II (APOC2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

APOC4-APOC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033434033).

BS2

High Homozygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001646.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC4	NM_001646.3	MANE Select	c.155G>A	p.Gly52Asp	missense	Exon 2 of 3	NP_001637.1	P55056
	APOC4-APOC2	NR_037932.1		n.195G>A		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOC4	ENST00000592954.2	TSL:1 MANE Select	c.155G>A	p.Gly52Asp	missense	Exon 2 of 3	ENSP00000468236.1	P55056
APOC4-APOC2	ENST00000589057.5	TSL:5	c.155G>A	p.Gly52Asp	missense	Exon 2 of 5	ENSP00000468139.1	K7ER74
APOC4	ENST00000896758.1		c.176G>A	p.Gly59Asp	missense	Exon 2 of 3	ENSP00000566817.1

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

949

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0368

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00578

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00657

AC:

1568

AN:

238704

AF XY:

0.00658

show subpopulations

Gnomad AFR exome

AF:

0.000393

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.00849

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00472

AC:

6870

AN:

1456640

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3489

AN XY:

724206

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33452

American (AMR)

AF:

0.00190

AC:

AN:

43106

Ashkenazi Jewish (ASJ)

AF:

0.00970

AC:

251

AN:

25870

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39570

South Asian (SAS)

AF:

0.00144

AC:

123

AN:

85274

European-Finnish (FIN)

AF:

0.0336

AC:

1786

AN:

53168

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00390

AC:

4332

AN:

1110212

Other (OTH)

AF:

0.00438

AC:

264

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

342

685

1027

1370

1712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00623

AC:

949

AN:

152274

Hom.:

Cov.:

AF XY:

0.00776

AC XY:

578

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41558

American (AMR)

AF:

0.00432

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0368

AC:

391

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00578

AC:

393

AN:

68018

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00451

Hom.:

Bravo

AF:

0.00320

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00631

AC:

766

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.3

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

-0.42

Sift4G

Benign

0.14

Polyphen

0.011

Vest4

0.12

MVP

0.29

ClinPred

0.0021

GERP RS

1.3

Varity_R

0.044

gMVP

0.085

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over