rs267606661

Variant names:

• chr19-44909101-C-G
• rs267606661
• NM_000041.4:c.805C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-44909101-C-G
• chr19-44909101-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP3 BS1_Supporting

The NM_000041.4(APOE):​c.805C>G​(p.Arg269Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000653 in 1,587,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.32
• Publications: 16 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: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1391 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00069 (990/1435384) while in subpopulation NFE AF = 0.000824 (910/1104338). AF 95% confidence interval is 0.000779. There are 0 homozygotes in GnomAdExome4. There are 484 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.805C>G	p.Arg269Gly	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.883C>G	p.Arg295Gly	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.805C>G	p.Arg269Gly	missense	Exon 4 of 4	NP_001289618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.805C>G	p.Arg269Gly	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000864831.1		c.859C>G	p.Arg287Gly	missense	Exon 5 of 5	ENSP00000534890.1
	APOE	ENST00000864832.1		c.856C>G	p.Arg286Gly	missense	Exon 5 of 5	ENSP00000534891.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000387 AC: 77 AN: 198936 AF XY: 0.000354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000619

Gnomad ASJ exome AF: 0.000219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000182

Gnomad NFE exome AF: 0.000533

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000690 AC: 990 AN: 1435384 Hom.: 0 Cov.: 33 AF XY: 0.000679 AC XY: 484 AN XY: 713280

African (AFR) AF: 0.000151 AC: 5 AN: 33120

American (AMR) AF: 0.000502 AC: 21 AN: 41820

Ashkenazi Jewish (ASJ) AF: 0.000233 AC: 6 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 38654

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83992

European-Finnish (FIN) AF: 0.000141 AC: 6 AN: 42568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.000824 AC: 910 AN: 1104338

Other (OTH) AF: 0.000688 AC: 41 AN: 59562

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74360

African (AFR) AF: 0.000121 AC: 5 AN: 41450

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000355

ExAC AF: 0.000200 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Alzheimer disease 2 (1)
-	1	-	APOE-related disorder (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Familial type 3 hyperlipoproteinemia (1)
-	1	-	Familial type 3 hyperlipoproteinemia;C0036489:Sea-blue histiocyte syndrome;C1843013:Alzheimer disease 3;C1847200:Alzheimer disease 4;C1863051:Alzheimer disease 2;C1864205:Age related macular degeneration 1;C2673196:Lipoprotein glomerulopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		0.55	P
Vest4		0.80
MVP		0.84
MPC		1.3
ClinPred		0.079	T
GERP RS		1.6
Varity_R		0.26
gMVP		0.84
Mutation Taster		=70/30	polymorphism

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: rs267606661; hg19: chr19-45412358;