19-44905579-T-G

Variant names:

• chr19-44905579-T-G
• rs405509
• NM_000041.4:c.-286T>G

Variant summary

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

The NM_000041.4(APOE):​c.-286T>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 152,040 control chromosomes in the GnomAD database, including 26,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: 𝑓 0.58 (26172 hom., cov: 31)
• Consequence: APOE NM_000041.4 upstream_gene
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.310
• Publications: 386 publications found

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]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.-286T>G		upstream_gene_variant		ENST00000252486.9	NP_000032.1
APOE	NM_001302688.2	c.-290T>G		upstream_gene_variant			NP_001289617.1
APOE	NM_001302691.2	c.-301T>G		upstream_gene_variant			NP_001289620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.-286T>G		upstream_gene_variant		1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000485628.2	n.-217T>G		upstream_gene_variant		1
APOE	ENST00000434152.5	c.-290T>G		upstream_gene_variant		2		ENSP00000413653.2
APOE	ENST00000446996.5	c.-301T>G		upstream_gene_variant		2		ENSP00000413135.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87415 AN: 151922 Hom.: 26137 Cov.: 31

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.577

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.576 AC: 87504 AN: 152040 Hom.: 26172 Cov.: 31 AF XY: 0.572 AC XY: 42525 AN XY: 74316

African (AFR) AF: 0.747 AC: 30987 AN: 41496

American (AMR) AF: 0.502 AC: 7673 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1853 AN: 3466

East Asian (EAS) AF: 0.306 AC: 1577 AN: 5158

South Asian (SAS) AF: 0.444 AC: 2140 AN: 4822

European-Finnish (FIN) AF: 0.557 AC: 5888 AN: 10570

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35512 AN: 67934

Other (OTH) AF: 0.576 AC: 1218 AN: 2114

Alfa AF: 0.531 Hom.: 68923

Bravo AF: 0.577

Asia WGS AF: 0.428 AC: 1492 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Warfarin response Other:1

Aug 31, 2010

Pharmacogenomics Lab, Chungbuk National University

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		0.31
PromoterAI		-0.0025	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs405509; hg19: chr19-45408836;