19-44945208-T-G

Variant names:

• chr19-44945208-T-G
• rs5167
• NM_001646.3:c.287T>G

Variant summary

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

The NM_001646.3(APOC4):​c.287T>G​(p.Leu96Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,613,606 control chromosomes in the GnomAD database, including 111,118 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 0.40 (12469 hom., cov: 31)
  • Exomes 𝑓: 0.36 (98649 hom.)
• Consequence: APOC4 NM_001646.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 89 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=6.150553E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC4	NM_001646.3	MANE Select	c.287T>G	p.Leu96Arg	missense	Exon 3 of 3	NP_001637.1
	APOC4-APOC2	NR_037932.1		n.327T>G		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC4	ENST00000592954.2	TSL:1 MANE Select	c.287T>G	p.Leu96Arg	missense	Exon 3 of 3	ENSP00000468236.1
	APOC4-APOC2	ENST00000589057.5	TSL:5	c.218+318T>G		intron	N/A	ENSP00000468139.1
	APOC4-APOC2	ENST00000585685.5	TSL:5	n.287T>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000467185.1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60730 AN: 151778 Hom.: 12440 Cov.: 31

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.400

GnomAD2 exomes AF: 0.394 AC: 99041 AN: 251326 AF XY: 0.385

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.364 AC: 532589 AN: 1461710 Hom.: 98649 Cov.: 45 AF XY: 0.362 AC XY: 263534 AN XY: 727176

African (AFR) AF: 0.440 AC: 14730 AN: 33476

American (AMR) AF: 0.467 AC: 20890 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9486 AN: 26130

East Asian (EAS) AF: 0.499 AC: 19794 AN: 39692

South Asian (SAS) AF: 0.324 AC: 27975 AN: 86248

European-Finnish (FIN) AF: 0.423 AC: 22576 AN: 53360

Middle Eastern (MID) AF: 0.356 AC: 2052 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392352 AN: 1111928

Other (OTH) AF: 0.376 AC: 22734 AN: 60394

GnomAD4 genome AF: 0.400 AC: 60815 AN: 151896 Hom.: 12469 Cov.: 31 AF XY: 0.403 AC XY: 29953 AN XY: 74236

African (AFR) AF: 0.448 AC: 18530 AN: 41398

American (AMR) AF: 0.428 AC: 6532 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1234 AN: 3468

East Asian (EAS) AF: 0.531 AC: 2740 AN: 5158

South Asian (SAS) AF: 0.346 AC: 1669 AN: 4824

European-Finnish (FIN) AF: 0.435 AC: 4598 AN: 10558

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24346 AN: 67926

Other (OTH) AF: 0.402 AC: 847 AN: 2108

Alfa AF: 0.370 Hom.: 51278

Bravo AF: 0.405

ESP6500AA AF: 0.459 AC: 2023

ESP6500EA AF: 0.358 AC: 3080

ExAC AF: 0.389 AC: 47234

Asia WGS AF: 0.454 AC: 1578 AN: 3478

EpiCase AF: 0.360

EpiControl AF: 0.358

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.018
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00032	N
MetaRNN	Benign	0.000062	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.2
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
ClinPred		0.0026	T
GERP RS		2.1
Varity_R		0.073
gMVP		0.030
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5167; hg19: chr19-45448465; COSMIC: COSV52990017; COSMIC: COSV52990017;