rs769446

Variant names:

• chr19-44905371-T-C
• rs769446
• ENST00000864817.1:c.-23-1231T>C

Variant summary

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

The ENST00000864817.1(APOE):​c.-23-1231T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 149,116 control chromosomes in the GnomAD database, including 452 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 0.071 (452 hom., cov: 32)
• Consequence: APOE ENST00000864817.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 74 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.097 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.-23-1231T>C		intron	N/A	ENSP00000534877.1
	APOE	ENST00000864820.1		c.-152T>C		upstream_gene	N/A	ENSP00000534879.1
	APOE	ENST00000864822.1		c.-616T>C		upstream_gene	N/A	ENSP00000534881.1

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10561 AN: 148988 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0537

Gnomad ASJ AF: 0.0722

Gnomad EAS AF: 0.0932

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0662

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.0771

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

GnomAD4 genome AF: 0.0708 AC: 10558 AN: 149116 Hom.: 452 Cov.: 32 AF XY: 0.0685 AC XY: 4988 AN XY: 72868

African (AFR) AF: 0.0359 AC: 1451 AN: 40394

American (AMR) AF: 0.0537 AC: 802 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.0722 AC: 249 AN: 3450

East Asian (EAS) AF: 0.0930 AC: 451 AN: 4848

South Asian (SAS) AF: 0.0621 AC: 292 AN: 4704

European-Finnish (FIN) AF: 0.0402 AC: 416 AN: 10346

Middle Eastern (MID) AF: 0.0534 AC: 14 AN: 262

European-Non Finnish (NFE) AF: 0.0990 AC: 6654 AN: 67200

Other (OTH) AF: 0.0788 AC: 163 AN: 2068

Alfa AF: 0.0881 Hom.: 128

Bravo AF: 0.0686

Asia WGS AF: 0.0960 AC: 334 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		-1.4
PromoterAI		0.028	Neutral

Splicing

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

Other links and lift over

dbSNP: rs769446; hg19: chr19-45408628;