chr19-44907654-T-G

Variant names:

• chr19-44907654-T-G
• rs769451
• NM_000041.4:c.44-106T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000041.4(APOE):​c.44-106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 992,904 control chromosomes in the GnomAD database, including 24 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 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (21 hom.)
• Consequence: APOE NM_000041.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652
• Publications: 10 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=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (786/152280) while in subpopulation NFE AF = 0.00769 (523/68020). AF 95% confidence interval is 0.00714. There are 3 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.44-106T>G		intron_variant	Intron 2 of 3	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.44-106T>G		intron_variant	Intron 2 of 3	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.44-106T>G		intron_variant	Intron 1 of 2	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.122-106T>G		intron_variant	Intron 2 of 3	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.44-106T>G		intron_variant	Intron 2 of 3	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.00630 AC: 5297 AN: 840624 Hom.: 21 AF XY: 0.00601 AC XY: 2603 AN XY: 433380

African (AFR) AF: 0.00181 AC: 38 AN: 21050

American (AMR) AF: 0.00516 AC: 180 AN: 34872

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 30 AN: 21668

East Asian (EAS) AF: 0.00 AC: 0 AN: 33048

South Asian (SAS) AF: 0.00155 AC: 105 AN: 67912

European-Finnish (FIN) AF: 0.00467 AC: 160 AN: 34270

Middle Eastern (MID) AF: 0.000773 AC: 3 AN: 3880

European-Non Finnish (NFE) AF: 0.00787 AC: 4596 AN: 584138

Other (OTH) AF: 0.00465 AC: 185 AN: 39786

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00514 AC XY: 383 AN XY: 74454

African (AFR) AF: 0.00125 AC: 52 AN: 41570

American (AMR) AF: 0.00536 AC: 82 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00769 AC: 523 AN: 68020

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00478

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.73
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs769451; hg19: chr19-45410911;