19-44905923-G-A

Position:

chr19-44905923-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001302688.2(APOE):c.55G>A(p.Asp19Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,296,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/14 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

APOE
NM_001302688.2 missense, splice_region

Scores

Splicing: ADA: 0.00009908

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.250

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 made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00725469).

BP6

Variant 19-44905923-G-A is Benign according to our data. Variant chr19-44905923-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1722323.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000572 (87/152180) while in subpopulation NFE AF= 0.000779 (53/68002). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.-24+82G>A		intron_variant		ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5
APOE	NM_001302688.2 link	c.55G>A	p.Asp19Asn	missense_variant, splice_region_variant	1/4		NP_001289617.1	P02649
APOE	NM_001302691.2 link	c.-39+82G>A		intron_variant			NP_001289620.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.-24+82G>A		intron_variant		1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000485628.2 link	n.46+82G>A		intron_variant		1
APOE	ENST00000434152.5 link	c.55G>A	p.Asp19Asn	missense_variant, splice_region_variant	1/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.-39+82G>A		intron_variant		2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000583

AC:

AN:

140542

Hom.:

AF XY:

0.000656

AC XY:

AN XY:

76164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000345

Gnomad ASJ exome

AF:

0.00412

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000330

Gnomad NFE exome

AF:

0.000598

Gnomad OTH exome

AF:

0.00124

GnomAD4 exome

AF:

0.000628

AC:

719

AN:

1144028

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

328

AN XY:

561122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000372

Gnomad4 ASJ exome

AF:

0.00493

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000220

Gnomad4 NFE exome

AF:

0.000646

Gnomad4 OTH exome

AF:

0.000802

GnomAD4 genome

AF:

0.000572

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000955

Hom.:

Bravo

AF:

0.000631

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000811

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alzheimer disease 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Sep 02, 2020

- -

APOE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial type 3 hyperlipoproteinemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Gain of function and loss of function are likely mechanisms of disease in this gene and are associated with APOE-related conditions. Gain of function has been suggested as the mechanism for Alzheimer disease and both gain of function and loss of function have been suggested as the mechanism for lipoprotein related conditions (PMIDs: 34058468, 33679311). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is only coding in the longest transcript (NM_001302688.1) but is non-coding in the ClinVar predominant and MANE select transcript NM_000041.3. The exon unique to NM_001302688.1 only has one variant in ClinVar which is classified as benign, and the expression of this transcript is generally lower than NM_000041.3 (GTex). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (97 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified once as a VUS in LOVD. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.4

DANN

Benign

0.76

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.95

REVEL

Benign

0.0080

MVP

0.69

ClinPred

0.0074

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000099

dbscSNV1_RF

Benign

0.0080

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over