rs769449

Positions:

• chr19-44906745-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000041.4(APOE):​c.43+78G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,460,964 control chromosomes in the GnomAD database, including 9,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (699 hom., cov: 31)
  • Exomes 𝑓: 0.12 (9129 hom.)
• Consequence: APOE NM_000041.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.335

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-44906745-G-A is Benign according to our data. Variant chr19-44906745-G-A is described in ClinVar as [Benign]. Clinvar id is 1264941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-44906745-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.43+78G>A		intron_variant		ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.43+78G>A		intron_variant		1	NM_000041.4	ENSP00000252486	P1

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12752 AN: 151926 Hom.: 693 Cov.: 31

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.0842

Gnomad SAS AF: 0.0756

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.116 AC: 151229 AN: 1308920 Hom.: 9129 Cov.: 20 AF XY: 0.114 AC XY: 75417 AN XY: 658794

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.0804

Gnomad4 ASJ exome AF: 0.0856

Gnomad4 EAS exome AF: 0.0778

Gnomad4 SAS exome AF: 0.0763

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0840 AC: 12773 AN: 152044 Hom.: 699 Cov.: 31 AF XY: 0.0880 AC XY: 6534 AN XY: 74292

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0762

Gnomad4 ASJ AF: 0.0867

Gnomad4 EAS AF: 0.0844

Gnomad4 SAS AF: 0.0752

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0986 Hom.: 1382

Bravo AF: 0.0743

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs769449; hg19: chr19-45410002;