rs121918395

Positions:

• chr19-44909032-C-A
• chr19-44909032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000041.4(APOE):​c.736C>A​(p.Arg246Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42164704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.736C>A	p.Arg246Ser	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.736C>A	p.Arg246Ser	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000434152.5			downstream_gene_variant		2		ENSP00000413653

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000694 AC: 1 AN: 144096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 78684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 688454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.061	T
Polyphen		0.90	P
Vest4		0.39
MutPred		0.63		Gain of phosphorylation at R246 (P = 0.0112);
MVP		0.88
MPC		1.5
ClinPred		0.68	D
GERP RS		1.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.15
gMVP		0.93

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: rs121918395; hg19: chr19-45412289;