19-44908706-G-T

Variant names:

• chr19-44908706-G-T
• rs11542035
• NM_000041.4:c.410G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000041.4(APOE):​c.410G>T​(p.Arg137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 5 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 5 ACMG points.

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in NM_000041.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.410G>T	p.Arg137Leu	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.488G>T	p.Arg163Leu	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.410G>T	p.Arg137Leu	missense	Exon 4 of 4	NP_001289618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.410G>T	p.Arg137Leu	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.410G>T	p.Arg137Leu	missense	Exon 3 of 3	ENSP00000410423.1
	APOE	ENST00000434152.5	TSL:2	c.488G>T	p.Arg163Leu	missense	Exon 4 of 4	ENSP00000413653.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.0060
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.35
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.45	T
Sift4G	Benign	0.096	T
Polyphen		0.99	D
Vest4		0.19
MutPred		0.72		Loss of disorder (P = 0.041)
MVP		0.89
MPC		1.8
ClinPred		0.84	D
GERP RS		1.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.41
gMVP		0.76
Mutation Taster		=60/40	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: rs11542035; hg19: chr19-45411963;