19-44907853-T-C

Position:

chr19-44907853-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000041.4(APOE):c.137T>C(p.Leu46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,614,020 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 6 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -2.79

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013945788).

BP6

Variant 19-44907853-T-C is Benign according to our data. Variant chr19-44907853-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242765.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (293/152306) while in subpopulation NFE AF= 0.00247 (168/68026). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.137T>C	p.Leu46Pro	missense_variant	3/4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.137T>C	p.Leu46Pro	missense_variant	3/4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.137T>C	p.Leu46Pro	missense_variant	2/3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.215T>C	p.Leu72Pro	missense_variant	3/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.137T>C	p.Leu46Pro	missense_variant	3/4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

293

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00251

AC:

629

AN:

250698

Hom.:

AF XY:

0.00243

AC XY:

329

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00770

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00203

AC:

2961

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1451

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00704

Gnomad4 NFE exome

AF:

0.00207

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152306

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00772

Gnomad4 NFE

AF:

0.00247

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00130

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 24126160, 24082139, 11068149, 22530123, 10213152, 23990795, 26802169, 16621646, 26206375, 24644280) -

Alzheimer disease 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS3. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2020

This alteration is classified as likely 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

Benign

0.24

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

2.3

DANN

Benign

0.94

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.5

M;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;N;.;N

REVEL

Uncertain

0.53

Sift

Benign

0.11

T;T;.;T

Sift4G

Benign

0.075

T;T;T;T

Polyphen

0.95

P;.;.;.

Vest4

0.58

MVP

0.84

MPC

1.6

ClinPred

0.025

GERP RS

-5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.71

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over