rs267606664

chr19-44908730-G-Achr19-44908730-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000041.4(APOE):c.434G>A(p.Gly145Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,560,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.98

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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000041.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.30857354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.434G>A	p.Gly145Asp	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.434G>A	p.Gly145Asp	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.434G>A	p.Gly145Asp	missense_variant	3/3	1
APOE	ENST00000434152.5	c.512G>A	p.Gly171Asp	missense_variant	4/4	2
APOE	ENST00000446996.5	c.434G>A	p.Gly145Asp	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000158 AC: 25 AN: 158024 Hom.: 0 AF XY: 0.000197 AC XY: 17 AN XY: 86226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000426

Gnomad FIN exome AF: 0.0000648

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000170 AC: 239 AN: 1408146 Hom.: 0 Cov.: 33 AF XY: 0.000154 AC XY: 107 AN XY: 695816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000547

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000498

Gnomad4 FIN exome AF: 0.0000413

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.000115 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.58	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.66	N;N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.11	T;T;.;T
Sift4G	Benign	0.068	T;T;D;T
Polyphen		1.0	D;.;.;.
Vest4		0.66
MVP		0.94
MPC		1.8
ClinPred		0.19	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.40

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: rs267606664; hg19: chr19-45411987;