19-44907853-T-C

Variant names:

• chr19-44907853-T-C
• rs769452
• NM_000041.4:c.137T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 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. 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:4
• Conservation: PhyloP100: -2.79
• Publications: 45 publications found

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 Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1391 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.
• 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 VariationId is 242765.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.137T>C	p.Leu46Pro	missense	Exon 3 of 4	NP_000032.1	A0A0S2Z3D5
	APOE	NM_001302688.2		c.215T>C	p.Leu72Pro	missense	Exon 3 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.137T>C	p.Leu46Pro	missense	Exon 3 of 4	NP_001289618.1	P02649

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.137T>C	p.Leu46Pro	missense	Exon 3 of 4	ENSP00000252486.3	P02649
	APOE	ENST00000425718.1	TSL:1	c.137T>C	p.Leu46Pro	missense	Exon 2 of 3	ENSP00000410423.1	E7ERP7
	APOE	ENST00000864831.1		c.191T>C	p.Leu64Pro	missense	Exon 4 of 5	ENSP00000534890.1

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

GnomAD2 exomes AF: 0.00251 AC: 629 AN: 250698 AF XY: 0.00243

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00704 AC: 376 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00207 AC: 2299 AN: 1111914

Other (OTH) AF: 0.00222 AC: 134 AN: 60372

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74480

African (AFR) AF: 0.000265 AC: 11 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00249 Hom.: 2

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	-	Alzheimer disease 4 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.53
Sift	Benign	0.11	T
Sift4G	Benign	0.075	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
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs769452; hg19: chr19-45411110;