chr19-44907187-G-A

Variant names:

• chr19-44907187-G-A
• rs769450
• ENST00000485628.2:n.632G>A

Variant summary

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

The ENST00000485628.2(APOE):​n.632G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 193,920 control chromosomes in the GnomAD database, including 14,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.39 (11839 hom., cov: 32)
  • Exomes 𝑓: 0.35 (2818 hom.)
• Consequence: APOE ENST00000485628.2 non_coding_transcript_exon
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.757
• Publications: 66 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000485628.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.43+520G>A		intron	N/A	NP_000032.1
	APOE	NM_001302688.2		c.121+520G>A		intron	N/A	NP_001289617.1
	APOE	NM_001302689.2		c.43+520G>A		intron	N/A	NP_001289618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000485628.2	TSL:1	n.632G>A		non_coding_transcript_exon	Exon 2 of 2
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.43+520G>A		intron	N/A	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.43+520G>A		intron	N/A	ENSP00000410423.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59281 AN: 151866 Hom.: 11834 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.406

GnomAD4 exome AF: 0.351 AC: 14727 AN: 41934 Hom.: 2818 Cov.: 0 AF XY: 0.351 AC XY: 7693 AN XY: 21930

African (AFR) AF: 0.373 AC: 497 AN: 1334

American (AMR) AF: 0.304 AC: 1095 AN: 3606

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 295 AN: 746

East Asian (EAS) AF: 0.217 AC: 631 AN: 2912

South Asian (SAS) AF: 0.341 AC: 1910 AN: 5604

European-Finnish (FIN) AF: 0.436 AC: 518 AN: 1188

Middle Eastern (MID) AF: 0.409 AC: 45 AN: 110

European-Non Finnish (NFE) AF: 0.367 AC: 8957 AN: 24378

Other (OTH) AF: 0.379 AC: 779 AN: 2056

GnomAD4 genome AF: 0.390 AC: 59316 AN: 151986 Hom.: 11839 Cov.: 32 AF XY: 0.391 AC XY: 29034 AN XY: 74282

African (AFR) AF: 0.379 AC: 15705 AN: 41440

American (AMR) AF: 0.323 AC: 4944 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1478 AN: 3470

East Asian (EAS) AF: 0.209 AC: 1075 AN: 5148

South Asian (SAS) AF: 0.354 AC: 1704 AN: 4818

European-Finnish (FIN) AF: 0.492 AC: 5202 AN: 10574

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27749 AN: 67938

Other (OTH) AF: 0.404 AC: 851 AN: 2106

Alfa AF: 0.390 Hom.: 14390

Bravo AF: 0.375

Asia WGS AF: 0.258 AC: 898 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Warfarin response Other:1

Aug 31, 2010

Pharmacogenomics Lab, Chungbuk National University

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

likely responsive

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.54
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769450; hg19: chr19-45410444;