rs776657518

Variant names:

• chr19-44945166-T-C
• rs776657518
• NM_001646.3:c.245T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-44945166-T-C
• chr19-44945166-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001646.3(APOC4):​c.245T>C​(p.Met82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M82V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APOC4 NM_001646.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25774896).

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.245T>C	p.Met82Thr	missense	Exon 3 of 3	NP_001637.1	P55056
	APOC4-APOC2	NR_037932.1		n.285T>C		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOC4	ENST00000592954.2	TSL:1 MANE Select	c.245T>C	p.Met82Thr	missense	Exon 3 of 3	ENSP00000468236.1	P55056
	APOC4-APOC2	ENST00000589057.5	TSL:5	c.218+276T>C		intron	N/A	ENSP00000468139.1	K7ER74
	APOC4	ENST00000896758.1		c.266T>C	p.Met89Thr	missense	Exon 3 of 3	ENSP00000566817.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111980

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
Sift4G	Uncertain	0.042	D
Polyphen		0.40	B
Vest4		0.49
MVP		0.35
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.18
gMVP		0.16
Mutation Taster		=75/25	polymorphism

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: rs776657518; hg19: chr19-45448423;