rs405509

Variant names:

• chr19-44905579-T-G
• rs405509
• ENST00000864822.1:c.-408T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-44905579-T-G
• chr19-44905579-T-A
• chr19-44905579-T-C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000864822.1(APOE):c.-408T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: ENST00000864822.1 is not a MANE Select or MANE Plus Clinical transcript for APOE; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.576 (AC=87,504) in the gnomAD database across 152,040 control chromosomes, including 26,172 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.74. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

• Frequency: Genomes: 𝑓 0.58 (26172 hom., cov: 31)
• Consequence: APOE ENST00000864822.1 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.310
• Publications: 391 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: Unknown, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipoproteinemia type 3

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

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

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

Classification according to ACMG Germline Pathogenicity v2019

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

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7398 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000864822.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.-286T>G		upstream_gene	N/A	NP_000032.1	P02649
	APOE	NM_001302688.2		c.-290T>G		upstream_gene	N/A	NP_001289617.1
	APOE	NM_001302691.2		c.-301T>G		upstream_gene	N/A	NP_001289620.1	A0A0S2Z3D5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000864822.1		c.-408T>G		5_prime_UTR	Exon 1 of 5	ENSP00000534881.1	P02649
	APOE	ENST00000864817.1		c.-23-1023T>G		intron	N/A	ENSP00000534877.1	P02649
	APOE	ENST00000864820.1		c.-24+80T>G		intron	N/A	ENSP00000534879.1	P02649

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

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.305 AC: 37173 AN: 121890

Turkish Variome AF: 0.530 AC: 819 AN: 1546 Hom.: 210

WBBC (Westlake BioBank for Chinese) pilot AF: 0.309 AC: 2771 AN: 8960 Hom.: 442

ABraOM SABE-WGS-1171 AF: 0.570 AC: 1335 AN: 2342 Hom.: 374

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		0.31
PromoterAI		-0.0026	Neutral

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs405509;

hg19: chr19-45408836;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar