rs440446

Positions:

• chr19-44905910-C-G
• chr19-44905910-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. 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. 11/12 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• 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 id is 1175067.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-44905910-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.-24+69C>G		intron_variant		ENST00000252486.9	NP_000032.1
APOE	NM_001302688.2	c.42C>G	p.Asn14Lys	missense_variant	1/4		NP_001289617.1
APOE	NM_001302691.2	c.-39+69C>G		intron_variant			NP_001289620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.-24+69C>G		intron_variant		1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000485628.2	n.46+69C>G		intron_variant		1
APOE	ENST00000434152.5	c.42C>G	p.Asn14Lys	missense_variant	1/4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.-39+69C>G		intron_variant		2		ENSP00000413135.1

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

GnomAD3 exomes AF: 0.604 AC: 84191 AN: 139394 Hom.: 26237 AF XY: 0.598 AC XY: 45221 AN XY: 75568

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 SAS exome AF: 0.521

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

Gnomad4 AFR exome AF: 0.864

Gnomad4 AMR exome AF: 0.545

Gnomad4 ASJ exome AF: 0.628

Gnomad4 EAS exome AF: 0.413

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.727

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.613

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

Gnomad4 AFR AF: 0.857

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.521

Gnomad4 FIN AF: 0.735

Gnomad4 NFE AF: 0.638

Gnomad4 OTH AF: 0.656

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
REVEL	Benign	0.013
ClinPred		0.0024	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs440446; hg19: chr19-45409167; COSMIC: COSV52986063; COSMIC: COSV52986063;