Genetic Variant APOC4:p.Leu36Arg (chr19-44944779-T-G) – 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_001646.3(APOC4):c.107T>G(p.Leu36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 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: 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 (MetaRNN=0.063256174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC4	NM_001646.3 link	c.107T>G	p.Leu36Arg	missense_variant	Exon 2 of 3	ENST00000592954.2	NP_001637.1	P55056
APOC4-APOC2	NR_037932.1 link	n.147T>G		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>G	p.Leu36Arg	missense_variant	Exon 2 of 3	1	NM_001646.3	ENSP00000468236.1	P55056
APOC4-APOC2	ENST00000589057.5 link	c.107T>G	p.Leu36Arg	missense_variant	Exon 2 of 5	5		ENSP00000468139.1	K7ER74
APOC4	ENST00000591600.1 link	c.107T>G	p.Leu36Arg	missense_variant	Exon 2 of 2	3		ENSP00000466444.1	K7EMC3
APOC4-APOC2	ENST00000585685.5 link	n.107T>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000467185.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110748

Other (OTH)

AF:

0.00

AC:

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.018

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.066

T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.27

.;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

-2.0

Sift4G

Uncertain

0.034

D;T;D

Polyphen

0.090

B;.;.

Vest4

0.15

MutPred

0.28

Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);

MVP

0.092

ClinPred

0.13

GERP RS

-4.9

Varity_R

0.056

gMVP

0.040

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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