rs11542030

chr19-44908910-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000041.4(APOE):c.614A>G(p.Gln205Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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. Q205Q) 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_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000041.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.26063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.614A>G	p.Gln205Arg	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.614A>G	p.Gln205Arg	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.614A>G	p.Gln205Arg	missense_variant	3/3	1
APOE	ENST00000434152.5	c.692A>G	p.Gln231Arg	missense_variant	4/4	2
APOE	ENST00000446996.5	c.614A>G	p.Gln205Arg	missense_variant	4/4	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Benign	0.079
Sift	Benign	0.092	T;T;.;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0040	B;.;.;.
Vest4		0.11
MutPred		0.69		Gain of methylation at Q205 (P = 0.0181);Gain of methylation at Q205 (P = 0.0181);.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11542030; hg19: chr19-45412167;