rs769455

chr19-44908783-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BS1 BS2

The NM_000041.4(APOE):c.487C>T(p.Arg163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,557,986 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0064 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (11 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:6
• Conservation: PhyloP100: 1.57

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 Benign. Variant got -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000041.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-44908784-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0120640695).
• BP6: Variant 19-44908783-C-T is Benign according to our data. Variant chr19-44908783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17851.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (978/152238) while in subpopulation AFR AF= 0.0209 (869/41564). AF 95% confidence interval is 0.0198. There are 15 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.487C>T	p.Arg163Cys	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.487C>T	p.Arg163Cys	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.487C>T	p.Arg163Cys	missense_variant	3/3	1
APOE	ENST00000434152.5	c.565C>T	p.Arg189Cys	missense_variant	4/4	2
APOE	ENST00000446996.5	c.487C>T	p.Arg163Cys	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152126 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00142 AC: 220 AN: 154854 Hom.: 3 AF XY: 0.000929 AC XY: 79 AN XY: 85004

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000854

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000817

Gnomad OTH exome AF: 0.000685

GnomAD4 exome AF: 0.000684 AC: 961 AN: 1405748 Hom.: 11 Cov.: 33 AF XY: 0.000593 AC XY: 412 AN XY: 694984

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000873

Gnomad4 FIN exome AF: 0.0000448

Gnomad4 NFE exome AF: 0.0000635

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152238 Hom.: 15 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74448

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00785

ESP6500AA AF: 0.0139 AC: 53

ESP6500EA AF: 0.000262 AC: 2

ExAC AF: 0.00123 AC: 134

Asia WGS AF: 0.00145 AC: 5 AN: 3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	This variant is associated with the following publications: (PMID: 24239320, 26377243, 3243553, 22069485, 20981092, 11500500, 24507774) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 14, 2020	- -

Familial type 3 hyperlipoproteinemia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1988	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000041.2:c.487C>T in the APOE gene has an allele frequency of 0.021 in African subpopulation in the gnomAD database. The p.Arg163Cys (NM_000041.2:c.487C>T) variant has been reported to be associated with type III hyperlipoproteinemia (PMID: 25502880; 26802169). In vitro functional studies suggest that the p.Arg163Cys variant may affect protein function (PMID: 26802169). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PP3. -

not specified Benign:2

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.069, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2021	- -

APOE-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D;D;.;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.49
MVP		0.98
MPC		1.9
ClinPred		0.037	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.72

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: rs769455; hg19: chr19-45412040;