Genetic Variant APOE:p.Thr11Ser (chr19-44906655-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000041.4(APOE):c.31A>T(p.Thr11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Variant links:

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]

APOE links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.120131135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.31A>T	p.Thr11Ser	missense_variant	Exon 2 of 4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9 link	c.31A>T	p.Thr11Ser	missense_variant	Exon 2 of 4	1	NM_000041.4	ENSP00000252486.3		P02649

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251476

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135914

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727244

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000112

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000298

Hom.:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.0

DANN

Benign

0.77

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.42

N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.20

T;T;.;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.0030

B;.;.;.

Vest4

0.13

MutPred

0.35

Gain of MoRF binding (P = 0.1086);Gain of MoRF binding (P = 0.1086);.;Gain of MoRF binding (P = 0.1086);

MVP

0.83

MPC

0.55

ClinPred

0.046

GERP RS

-5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.035

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over