dbSNP rs397514254: APOE:p.Glu139_Gly145dup (chr19-44908706-G-GCGGCGAGGTGCAGGCCATGCT) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM4PP5

The NM_000041.4(APOE):c.415_435dupGAGGTGCAGGCCATGCTCGGC(p.Glu139_Gly145dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,626 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

APOE
NM_000041.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.15

Publications

1 publications found

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

APOE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000041.4

PM4

Nonframeshift variant in NON repetitive region in NM_000041.4.

PP5

Variant 19-44908706-G-GCGGCGAGGTGCAGGCCATGCT is Pathogenic according to our data. Variant chr19-44908706-G-GCGGCGAGGTGCAGGCCATGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 17853.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.415_435dupGAGGTGCAGGCCATGCTCGGC	p.Glu139_Gly145dup	conservative_inframe_insertion	Exon 4 of 4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.415_435dupGAGGTGCAGGCCATGCTCGGC	p.Glu139_Gly145dup	conservative_inframe_insertion	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.415_435dupGAGGTGCAGGCCATGCTCGGC	p.Glu139_Gly145dup	conservative_inframe_insertion	Exon 3 of 3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.493_513dupGAGGTGCAGGCCATGCTCGGC	p.Glu165_Gly171dup	conservative_inframe_insertion	Exon 4 of 4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.415_435dupGAGGTGCAGGCCATGCTCGGC	p.Glu139_Gly145dup	conservative_inframe_insertion	Exon 4 of 4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1407626

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

695500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32036

American (AMR)

AF:

0.00

AC:

AN:

36344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

36348

South Asian (SAS)

AF:

0.00

AC:

AN:

80410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084646

Other (OTH)

AF:

0.00

AC:

AN:

58322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Familial type 3 hyperlipoproteinemia

Pathogenic:1

Apr 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=81/19

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over