19-44905910-C-G

Variant names:

• chr19-44905910-C-G
• rs440446
• NM_000041.4:c.-24+69C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001302688.2(APOE):​c.42C>G​(p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,293,628 control chromosomes in the GnomAD database, including 269,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (37025 hom., cov: 29)
  • Exomes 𝑓: 0.63 (232051 hom.)
• Consequence: APOE NM_001302688.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -2.66
• Publications: 112 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 -13 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: -1.1126 (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=9.173705E-7).
• BP6: Variant 19-44905910-C-G is Benign according to our data. Variant chr19-44905910-C-G is described in ClinVar as Benign. ClinVar VariationId is 1175067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302688.2. 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.-24+69C>G		intron	N/A	NP_000032.1	A0A0S2Z3D5
	APOE	NM_001302688.2		c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	NP_001289617.1
	APOE	NM_001302691.2		c.-39+69C>G		intron	N/A	NP_001289620.1	A0A0S2Z3D5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.-24+69C>G		intron	N/A	ENSP00000252486.3	P02649
	APOE	ENST00000485628.2	TSL:1	n.46+69C>G		intron	N/A
	APOE	ENST00000434152.5	TSL:2	c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	ENSP00000413653.2	H0Y7L5

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104386 AN: 151714 Hom.: 36967 Cov.: 29

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.604 AC: 84191 AN: 139394 AF XY: 0.598

Gnomad AFR exome AF: 0.863

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.629

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.635 AC: 724609 AN: 1141796 Hom.: 232051 Cov.: 41 AF XY: 0.630 AC XY: 352673 AN XY: 560016

African (AFR) AF: 0.864 AC: 20217 AN: 23408

American (AMR) AF: 0.545 AC: 14335 AN: 26288

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 9764 AN: 15552

East Asian (EAS) AF: 0.413 AC: 5063 AN: 12264

South Asian (SAS) AF: 0.523 AC: 39524 AN: 75558

European-Finnish (FIN) AF: 0.727 AC: 19828 AN: 27270

Middle Eastern (MID) AF: 0.556 AC: 1682 AN: 3026

European-Non Finnish (NFE) AF: 0.642 AC: 589003 AN: 917346

Other (OTH) AF: 0.613 AC: 25193 AN: 41084

GnomAD4 genome AF: 0.688 AC: 104514 AN: 151832 Hom.: 37025 Cov.: 29 AF XY: 0.688 AC XY: 51042 AN XY: 74182

African (AFR) AF: 0.857 AC: 35528 AN: 41440

American (AMR) AF: 0.590 AC: 9007 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2092 AN: 5126

South Asian (SAS) AF: 0.521 AC: 2501 AN: 4800

European-Finnish (FIN) AF: 0.735 AC: 7742 AN: 10540

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43318 AN: 67890

Other (OTH) AF: 0.656 AC: 1380 AN: 2104

Alfa AF: 0.622 Hom.: 7747

Bravo AF: 0.684

TwinsUK AF: 0.654 AC: 2426

ALSPAC AF: 0.667 AC: 2569

ExAC AF: 0.542 AC: 10611

Asia WGS AF: 0.563 AC: 1961 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.77
DANN	Benign	0.51
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.7
REVEL	Benign	0.013
ClinPred		0.0024	T
GERP RS		-3.6
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs440446; hg19: chr19-45409167; COSMIC: COSV52986063; COSMIC: COSV52986063;