19-44945208-T-G

Position:

• chr19-44945208-T-G

Variant summary

Our verdict is Benign. Variant got -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. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

APOC4-APOC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC4	NM_001646.3	c.287T>G	p.Leu96Arg	missense_variant	3/3	ENST00000592954.2	NP_001637.1
APOC4-APOC2	NR_037932.1	n.327T>G		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC4	ENST00000592954.2	c.287T>G	p.Leu96Arg	missense_variant	3/3	1	NM_001646.3	ENSP00000468236.1
APOC4-APOC2	ENST00000589057.5	c.218+318T>G		intron_variant		5		ENSP00000468139.1
APOC4-APOC2	ENST00000585685.5	n.287T>G		non_coding_transcript_exon_variant	3/6	5		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

GnomAD3 exomes AF: 0.394 AC: 99041 AN: 251326 Hom.: 20156 AF XY: 0.385 AC XY: 52344 AN XY: 135842

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 SAS exome AF: 0.316

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

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.376

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

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.402

Alfa AF: 0.363 Hom.: 25574

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 v4.3

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
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

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

Publications

LitVar

Other links and lift over

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