19-44944779-T-C

Position:

• chr19-44944779-T-C

Variant summary

Our verdict is Benign. Variant got -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. 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 0.60 (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

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=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/exons	MANE	Protein	UniProt
APOC4	NM_001646.3	c.107T>C	p.Leu36Pro	missense_variant	2/3	ENST00000592954.2	NP_001637.1
APOC4-APOC2	NR_037932.1	n.147T>C		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC4	ENST00000592954.2	c.107T>C	p.Leu36Pro	missense_variant	2/3	1	NM_001646.3	ENSP00000468236.1
APOC4-APOC2	ENST00000589057.5	c.107T>C	p.Leu36Pro	missense_variant	2/5	5		ENSP00000468139.1
APOC4	ENST00000591600.1	c.107T>C	p.Leu36Pro	missense_variant	2/2	3		ENSP00000466444.1
APOC4-APOC2	ENST00000585685.5	n.107T>C		non_coding_transcript_exon_variant	2/6	5		ENSP00000467185.1

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

GnomAD3 exomes AF: 0.589 AC: 144059 AN: 244748 Hom.: 43824 AF XY: 0.579 AC XY: 76570 AN XY: 132290

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 SAS exome AF: 0.623

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

Gnomad4 AFR exome AF: 0.716

Gnomad4 AMR exome AF: 0.756

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.687

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.509

Gnomad4 OTH exome AF: 0.554

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

Gnomad4 AFR AF: 0.713

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.640

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.512

Gnomad4 OTH AF: 0.568

Alfa AF: 0.529 Hom.: 43176

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	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0040
DANN	Benign	0.56
DEOGEN2	Benign	0.023	T;.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.17	.;T;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.75	N;.;.
Sift4G	Uncertain	0.048	D;T;T
Polyphen		0.0	B;.;.
Vest4		0.025
ClinPred		0.0055	T
GERP RS		-4.9
Varity_R		0.063
gMVP		0.030

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

LitVar

Other links and lift over

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