19-44905579-T-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The ENST00000864822.1(APOE):c.-408T>A 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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: APOE ENST00000864822.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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).

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>A	upstream_gene	N/A	Prot: NP_000032.1 UniProt:
	APOE NM_001302688.2		c.-290T>A	upstream_gene	N/A	Prot: NP_001289617.1
	APOE NM_001302691.2		c.-301T>A	upstream_gene	N/A	Prot: NP_001289620.1 UniProt:

APOE NM_000041.4

MANE Select

HGVSc / HGVSpc.-286T>A

Exon rankN/A

upstream_gene

Prot: NP_000032.1UniProt: P02649A0A0S2Z3D5

APOE NM_001302688.2

HGVSc / HGVSpc.-290T>A

Exon rankN/A

upstream_gene

Prot: NP_001289617.1

APOE NM_001302691.2

HGVSc / HGVSpc.-301T>A

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>A	5_prime_UTR	Exon 1 of 5	Prot: ENSP00000534881.1 UniProt:
	APOE ENST00000864817.1		c.-23-1023T>A	intron	Intron 1 of 3	Prot: ENSP00000534877.1 UniProt:
	APOE ENST00000864820.1		c.-24+80T>A	intron	Intron 1 of 3	Prot: ENSP00000534879.1 UniProt:

APOE ENST00000864822.1

HGVSc / HGVSpc.-408T>A

Exon rankExon 1 of 5

5_prime_UTR

Prot: ENSP00000534881.1UniProt: P02649

APOE ENST00000864817.1

HGVSc / HGVSpc.-23-1023T>A

Exon rankIntron 1 of 3

intron

Prot: ENSP00000534877.1UniProt: P02649

APOE ENST00000864820.1

HGVSc / HGVSpc.-24+80T>A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

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

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.5
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.76
GPN-Star LLR	N/A	2.4
GPN-Star score	N/A	-2.0
PhyloP100	Benign	0.31
PromoterAI	N/A	-0.015	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