Genetic Variant APOC4:p.Leu36Pro (chr19-44944779-T-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_001646.3(APOC4):c.107T>C(p.Leu36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,610,240 control chromosomes in the GnomAD database, including 240,998 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.60 ( 27750 hom., cov: 30)

Exomes 𝑓: 0.54 ( 213248 hom. )

Consequence

APOC4
NM_001646.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.98

Publications

47 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0255336E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC4	NM_001646.3 link	c.107T>C	p.Leu36Pro	missense_variant	Exon 2 of 3	ENST00000592954.2	NP_001637.1	P55056
APOC4-APOC2	NR_037932.1 link	n.147T>C		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOC4	ENST00000592954.2 link	c.107T>C	p.Leu36Pro	missense_variant	Exon 2 of 3	1	NM_001646.3	ENSP00000468236.1	P55056
APOC4-APOC2	ENST00000589057.5 link	c.107T>C	p.Leu36Pro	missense_variant	Exon 2 of 5	5		ENSP00000468139.1	K7ER74
APOC4	ENST00000591600.1 link	c.107T>C	p.Leu36Pro	missense_variant	Exon 2 of 2	3		ENSP00000466444.1	K7EMC3
APOC4-APOC2	ENST00000585685.5 link	n.107T>C		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000467185.1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90286

AN:

151698

Hom.:

27707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.713

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.663

Gnomad ASJ

AF:

0.475

Gnomad EAS

AF:

0.702

Gnomad SAS

AF:

0.642

Gnomad FIN

AF:

0.567

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.512

Gnomad OTH

AF:

0.567

GnomAD2 exomes

AF:

0.589

AC:

144059

AN:

244748

AF XY:

0.579

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.480

Gnomad EAS exome

AF:

0.690

Gnomad FIN exome

AF:

0.569

Gnomad NFE exome

AF:

0.505

Gnomad OTH exome

AF:

0.551

GnomAD4 exome

AF:

0.536

AC:

781927

AN:

1458424

Hom.:

213248

Cov.:

AF XY:

0.537

AC XY:

389231

AN XY:

725256

show subpopulations

African (AFR)

AF:

0.716

AC:

23967

AN:

33456

American (AMR)

AF:

0.756

AC:

33313

AN:

44066

Ashkenazi Jewish (ASJ)

AF:

0.483

AC:

12558

AN:

26024

East Asian (EAS)

AF:

0.687

AC:

27201

AN:

39580

South Asian (SAS)

AF:

0.623

AC:

53437

AN:

85736

European-Finnish (FIN)

AF:

0.564

AC:

30001

AN:

53168

Middle Eastern (MID)

AF:

0.508

AC:

2838

AN:

5584

European-Non Finnish (NFE)

AF:

0.509

AC:

565211

AN:

1110554

Other (OTH)

AF:

0.554

AC:

33401

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

20443

40886

61328

81771

102214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16582

33164

49746

66328

82910

<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:

0.595

AC:

90379

AN:

151816

Hom.:

27750

Cov.:

AF XY:

0.599

AC XY:

44432

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.713

AC:

29503

AN:

41374

American (AMR)

AF:

0.663

AC:

10107

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

1647

AN:

3468

East Asian (EAS)

AF:

0.702

AC:

3589

AN:

5112

South Asian (SAS)

AF:

0.640

AC:

3089

AN:

4826

European-Finnish (FIN)

AF:

0.567

AC:

5983

AN:

10554

Middle Eastern (MID)

AF:

0.462

AC:

135

AN:

292

European-Non Finnish (NFE)

AF:

0.512

AC:

34764

AN:

67934

Other (OTH)

AF:

0.568

AC:

1193

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1778

3557

5335

7114

8892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.538

Hom.:

66305

Bravo

AF:

0.608

ESP6500AA

AF:

0.716

AC:

3152

ESP6500EA

AF:

0.513

AC:

4412

ExAC

AF:

0.578

AC:

70137

Asia WGS

AF:

0.687

AC:

2388

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0040

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.023

T;.;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.17

.;T;T

MetaRNN

Benign

0.0000010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

N;.;.

PhyloP100

-2.0

Sift4G

Uncertain

0.048

D;T;T

Polyphen

0.0

B;.;.

Vest4

0.025

ClinPred

0.0055

GERP RS

-4.9

Varity_R

0.063

gMVP

0.030

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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