19-44905307-A-T

Variant names:

• chr19-44905307-A-T
• rs449647
• ENST00000864817.1:c.-23-1295A>T

Variant summary

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

The ENST00000864817.1(APOE):​c.-23-1295A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 150,672 control chromosomes in the GnomAD database, including 3,648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3648 hom., cov: 32)
• Consequence: APOE ENST00000864817.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 141 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000864817.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000864817.1		c.-23-1295A>T		intron	N/A	ENSP00000534877.1
	APOE	ENST00000864820.1		c.-216A>T		upstream_gene	N/A	ENSP00000534879.1
	APOE	ENST00000864822.1		c.-680A>T		upstream_gene	N/A	ENSP00000534881.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31386 AN: 150554 Hom.: 3639 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.209 AC: 31417 AN: 150672 Hom.: 3648 Cov.: 32 AF XY: 0.206 AC XY: 15146 AN XY: 73602

African (AFR) AF: 0.298 AC: 12191 AN: 40968

American (AMR) AF: 0.224 AC: 3383 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 962 AN: 3458

East Asian (EAS) AF: 0.0303 AC: 154 AN: 5090

South Asian (SAS) AF: 0.209 AC: 994 AN: 4766

European-Finnish (FIN) AF: 0.121 AC: 1248 AN: 10300

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11797 AN: 67690

Other (OTH) AF: 0.234 AC: 490 AN: 2098

Alfa AF: 0.202 Hom.: 386

Bravo AF: 0.216

Asia WGS AF: 0.128 AC: 443 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.81
PhyloP100		0.55
PromoterAI		0.035	Neutral

Splicing

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

Other links and lift over

dbSNP: rs449647; hg19: chr19-45408564;