chr19-44906745-G-A

Variant names:

• chr19-44906745-G-A
• rs769449
• NM_000041.4:c.43+78G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 233 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1264941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000041.4. 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
	APOE	NM_000041.4	MANE Select	c.43+78G>A		intron	N/A	NP_000032.1	A0A0S2Z3D5
	APOE	NM_001302688.2		c.121+78G>A		intron	N/A	NP_001289617.1
	APOE	NM_001302689.2		c.43+78G>A		intron	N/A	NP_001289618.1	P02649

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.43+78G>A		intron	N/A	ENSP00000252486.3	P02649
	APOE	ENST00000425718.1	TSL:1	c.43+78G>A		intron	N/A	ENSP00000410423.1	E7ERP7
	APOE	ENST00000485628.2	TSL:1	n.190G>A		non_coding_transcript_exon	Exon 2 of 2

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

African (AFR) AF: 0.0173 AC: 523 AN: 30256

American (AMR) AF: 0.0804 AC: 3573 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 2149 AN: 25104

East Asian (EAS) AF: 0.0778 AC: 3031 AN: 38956

South Asian (SAS) AF: 0.0763 AC: 6343 AN: 83154

European-Finnish (FIN) AF: 0.170 AC: 8847 AN: 51976

Middle Eastern (MID) AF: 0.0325 AC: 163 AN: 5016

European-Non Finnish (NFE) AF: 0.124 AC: 121039 AN: 974658

Other (OTH) AF: 0.100 AC: 5561 AN: 55382

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

African (AFR) AF: 0.0214 AC: 889 AN: 41504

American (AMR) AF: 0.0762 AC: 1163 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3472

East Asian (EAS) AF: 0.0844 AC: 435 AN: 5154

South Asian (SAS) AF: 0.0752 AC: 363 AN: 4824

European-Finnish (FIN) AF: 0.175 AC: 1843 AN: 10556

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7514 AN: 67950

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0996 Hom.: 3200

Bravo AF: 0.0743

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		0.34
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs769449; hg19: chr19-45410002;