chr19-44907853-T-C

Position:

• chr19-44907853-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Synonymous variant affecting the same amino acid position (i.e. L46L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -2.79

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 -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: {Likely_benign=2, Uncertain_significance=3, 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	UniProt
APOE	NM_000041.4	c.137T>C	p.Leu46Pro	missense_variant	3/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.137T>C	p.Leu46Pro	missense_variant	3/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.137T>C	p.Leu46Pro	missense_variant	2/3	1
APOE	ENST00000434152.5	c.215T>C	p.Leu72Pro	missense_variant	3/4	2
APOE	ENST00000446996.5	c.137T>C	p.Leu46Pro	missense_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152188 Hom.: 0 Cov.: 32

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.: 4 AF XY: 0.00243 AC XY: 329 AN XY: 135650

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.: 6 Cov.: 32 AF XY: 0.00200 AC XY: 1451 AN XY: 727148

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.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74480

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.: 1

Bravo AF: 0.00130

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

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) -
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	- -

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	T
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	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.5	M;.;.;.
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs769452; hg19: chr19-45411110;