Genetic Variant APOE:c.44-106T>G (chr19-44907654-T-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000041.4(APOE):c.44-106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 992,904 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 21 hom. )

Consequence

APOE
NM_000041.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.652

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-44907654-T-G is Benign according to our data. Variant chr19-44907654-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (786/152280) while in subpopulation NFE AF = 0.00769 (523/68020). AF 95% confidence interval is 0.00714. There are 3 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.44-106T>G		intron_variant	Intron 2 of 3	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.44-106T>G	intron_variant	Intron 2 of 3	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.44-106T>G	intron_variant	Intron 1 of 2	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.122-106T>G	intron_variant	Intron 2 of 3	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.44-106T>G	intron_variant	Intron 2 of 3	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.00516

AC:

785

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00769

Gnomad OTH

AF:

0.00431

GnomAD4 exome

AF:

0.00630

AC:

5297

AN:

840624

Hom.:

AF XY:

0.00601

AC XY:

2603

AN XY:

433380

show subpopulations

Gnomad4 AFR exome

AF:

0.00181

AC:

AN:

21050

Gnomad4 AMR exome

AF:

0.00516

AC:

180

AN:

34872

Gnomad4 ASJ exome

AF:

0.00138

AC:

AN:

21668

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

33048

Gnomad4 SAS exome

AF:

0.00155

AC:

105

AN:

67912

Gnomad4 FIN exome

AF:

0.00467

AC:

160

AN:

34270

Gnomad4 NFE exome

AF:

0.00787

AC:

4596

AN:

584138

Gnomad4 Remaining exome

AF:

0.00465

AC:

185

AN:

39786

Heterozygous variant carriers

291

582

872

1163

1454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00516

AC:

786

AN:

152280

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

383

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00125

AC:

0.0012509

AN:

0.0012509

Gnomad4 AMR

AF:

0.00536

AC:

0.00536228

AN:

0.00536228

Gnomad4 ASJ

AF:

0.00173

AC:

0.0017311

AN:

0.0017311

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00166

AC:

0.00165631

AN:

0.00165631

Gnomad4 FIN

AF:

0.00650

AC:

0.00650207

AN:

0.00650207

Gnomad4 NFE

AF:

0.00769

AC:

0.00768892

AN:

0.00768892

Gnomad4 OTH

AF:

0.00427

AC:

0.0042654

AN:

0.0042654

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00447

Hom.:

Bravo

AF:

0.00478

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.3

DANN

Benign

0.73

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over