rs121918399

chr19-44907843-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000041.4(APOE):c.127C>T(p.Arg43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.34

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-44907843-C-T is Pathogenic according to our data. Variant chr19-44907843-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.127C>T	p.Arg43Cys	missense_variant	3/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.127C>T	p.Arg43Cys	missense_variant	3/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.127C>T	p.Arg43Cys	missense_variant	2/3	1
APOE	ENST00000434152.5	c.205C>T	p.Arg69Cys	missense_variant	3/4	2
APOE	ENST00000446996.5	c.127C>T	p.Arg43Cys	missense_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250366 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lipoprotein glomerulopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Precision Medicine Center, Zhengzhou University	-	PM2:at extremely low frequency in gnomAD PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP4:Patient's phenotype is highly specific for a disease -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 10432380). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.60; 3Cnet: 0.07). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017880 / PMID: 10529625). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 13, 2007	- -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.55	N;.;.;.
MutationTaster	Benign	0.99	A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D;D;.;D
Sift4G	Uncertain	0.021	D;D;T;D
Polyphen		0.68	P;.;.;.
Vest4		0.76
MutPred		0.78		Gain of catalytic residue at W44 (P = 0.001);Gain of catalytic residue at W44 (P = 0.001);.;Gain of catalytic residue at W44 (P = 0.001);
MVP		0.93
MPC		0.92
ClinPred		0.32	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.50

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: rs121918399; hg19: chr19-45411100; COSMIC: COSV52986041; COSMIC: COSV52986041;