19-44944779-T-C

Variant names:

• chr19-44944779-T-C
• rs1132899
• NM_001646.3:c.107T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• Publications: 47 publications found

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-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]

ACMG classification

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.

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.107T>C	p.Leu36Pro	missense	Exon 2 of 3	NP_001637.1	P55056
	APOC4-APOC2	NR_037932.1		n.147T>C		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC4	ENST00000592954.2	TSL:1 MANE Select	c.107T>C	p.Leu36Pro	missense	Exon 2 of 3	ENSP00000468236.1	P55056
	APOC4-APOC2	ENST00000589057.5	TSL:5	c.107T>C	p.Leu36Pro	missense	Exon 2 of 5	ENSP00000468139.1	K7ER74
	APOC4	ENST00000896758.1		c.128T>C	p.Leu43Pro	missense	Exon 2 of 3	ENSP00000566817.1

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90286 AN: 151698 Hom.: 27707 Cov.: 30

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

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.: 57 AF XY: 0.537 AC XY: 389231 AN XY: 725256

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

GnomAD4 genome AF: 0.595 AC: 90379 AN: 151816 Hom.: 27750 Cov.: 30 AF XY: 0.599 AC XY: 44432 AN XY: 74164

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0040
DANN	Benign	0.56
DEOGEN2	Benign	0.023	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.75	N
PhyloP100		-2.0
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.025
ClinPred		0.0055	T
GERP RS		-4.9
Varity_R		0.063
gMVP		0.030
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1132899; hg19: chr19-45448036; COSMIC: COSV52990363; COSMIC: COSV52990363;