rs11542030

Variant names:

• chr19-44908910-A-G
• rs11542030
• NM_000041.4:c.614A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001302688.2(APOE):​c.692A>G​(p.Gln231Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q231Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOE NM_001302688.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• Publications: 1 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.

• 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: -1.1126 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26063).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302688.2. 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.614A>G	p.Gln205Arg	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.692A>G	p.Gln231Arg	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.614A>G	p.Gln205Arg	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.614A>G	p.Gln205Arg	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.614A>G	p.Gln205Arg	missense	Exon 3 of 3	ENSP00000410423.1
	APOE	ENST00000864831.1		c.668A>G	p.Gln223Arg	missense	Exon 5 of 5	ENSP00000534890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1316478 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 646710

African (AFR) AF: 0.00 AC: 0 AN: 27030

American (AMR) AF: 0.00 AC: 0 AN: 24478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21052

East Asian (EAS) AF: 0.00 AC: 0 AN: 32714

South Asian (SAS) AF: 0.00 AC: 0 AN: 69338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3804

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051186

Other (OTH) AF: 0.00 AC: 0 AN: 54464

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.45
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.079
Sift	Benign	0.092	T
Sift4G	Benign	0.25	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.69		Gain of methylation at Q205 (P = 0.0181)
MVP		0.90
MPC		0.73
ClinPred		0.075	T
GERP RS		1.6
Varity_R		0.058
gMVP		0.39
Mutation Taster		=72/28	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: rs11542030; hg19: chr19-45412167;