chr19-44905579-T-G

Variant names:

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

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: 109 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

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		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	Prot: NP_000032.1 UniProt:
	APOE NM_001302688.2		c.-290T>G	upstream_gene	N/A	Prot: NP_001289617.1
	APOE NM_001302691.2		c.-301T>G	upstream_gene	N/A	Prot: NP_001289620.1 UniProt:

APOE NM_000041.4

MANE Select

HGVSc / HGVSpc.-286T>G

Exon rankN/A

upstream_gene

Prot: NP_000032.1UniProt: P02649A0A0S2Z3D5

APOE NM_001302688.2

HGVSc / HGVSpc.-290T>G

Exon rankN/A

upstream_gene

Prot: NP_001289617.1

APOE NM_001302691.2

HGVSc / HGVSpc.-301T>G

Exon rankN/A

upstream_gene

Prot: NP_001289620.1UniProt: A0A0S2Z3D5P02649

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	Prot: ENSP00000534881.1 UniProt:
	APOE ENST00000864817.1		c.-23-1023T>G	intron	Intron 1 of 3	Prot: ENSP00000534877.1 UniProt:
	APOE ENST00000864820.1		c.-24+80T>G	intron	Intron 1 of 3	Prot: ENSP00000534879.1 UniProt:

APOE ENST00000864822.1

HGVSc / HGVSpc.-408T>G

Exon rankExon 1 of 5

5_prime_UTR

Prot: ENSP00000534881.1UniProt: P02649

APOE ENST00000864817.1

HGVSc / HGVSpc.-23-1023T>G

Exon rankIntron 1 of 3

intron

Prot: ENSP00000534877.1UniProt: P02649

APOE ENST00000864820.1

HGVSc / HGVSpc.-24+80T>G

Exon rankIntron 1 of 3

intron

Prot: ENSP00000534879.1UniProt: P02649

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.575	AC:87415	Hom:26137	AN:151922	Cov:31
GnomAD4 genome	AF: 0.576	AC:87504	Hom:26172	AN:152040	Cov:31
TOPMed (Bravo)	AF: 0.577	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.534	AC:274437	Hom:74452	AN:513630	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.570	AC:1335	Hom:374	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.295	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.573	AC:172	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.428	AC:1492	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.281	AC:2033	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.506	AC:89	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.305	AC:37173	Hom:5680	AN:121890	Cov:
Turkish Variome	AF: 0.530	AC:819	Hom:210	AN:1546	Cov:
UK10K	AF: 0.536	AC:4057	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.309	AC:2771	Hom:442	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.2
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.77
GPN-Star LLR	N/A	6.3
GPN-Star score	N/A	1.9
PhyloP100	Benign	0.31
PromoterAI	N/A	-0.0025	Neutral

Showing 8 of 8 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs405509;

hg19: chr19-45408836;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar