rs199768005

Positions:

• chr19-44909057-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_000041.4(APOE):​c.761T>A​(p.Val254Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,562,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 B:2
• Conservation: PhyloP100: 0.0590

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 -7 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 8 benign (71%) in NM_000041.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.034093946).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000473 (72/152198) while in subpopulation NFE AF= 0.000765 (52/67976). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.761T>A	p.Val254Glu	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.761T>A	p.Val254Glu	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000434152.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

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: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000452 AC: 75 AN: 165832 Hom.: 1 AF XY: 0.000494 AC XY: 45 AN XY: 91184

Gnomad AFR exome AF: 0.000214

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000215

Gnomad NFE exome AF: 0.000999

Gnomad OTH exome AF: 0.000214

GnomAD4 exome AF: 0.000659 AC: 929 AN: 1410160 Hom.: 2 Cov.: 33 AF XY: 0.000643 AC XY: 449 AN XY: 698452

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000742

Gnomad4 NFE exome AF: 0.000829

Gnomad4 OTH exome AF: 0.000255

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74426

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.000427

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00119 AC: 10

ExAC AF: 0.000431 AC: 51

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as APOE3-Jacksonville, APOE3-Jac, and p.(V236E); Has not been previously published in association with dyslipidemia to our knowledge; This variant is associated with the following publications: (PMID: 25560647, 32808727, 34058468, 24607147, 34586832) -

Familial type 3 hyperlipoproteinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1993

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.89	P
Vest4		0.43
MVP		0.90
MPC		1.8
ClinPred		0.12	T
GERP RS		3.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.33
gMVP		0.82

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: rs199768005; hg19: chr19-45412314; COSMIC: COSV105005979; COSMIC: COSV105005979;