19-44907807-G-A

Position:

chr19-44907807-G-A

Variant summary

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

The NM_000041.4(APOE):c.91G>A(p.Glu31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03719899).

BP6

Variant 19-44907807-G-A is Benign according to our data. Variant chr19-44907807-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440842.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000473 (72/152304) while in subpopulation AMR AF= 0.00314 (48/15302). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.91G>A	p.Glu31Lys	missense_variant	3/4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.91G>A	p.Glu31Lys	missense_variant	3/4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.91G>A	p.Glu31Lys	missense_variant	2/3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.169G>A	p.Glu57Lys	missense_variant	3/4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.91G>A	p.Glu31Lys	missense_variant	3/4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249636

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000235

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000473

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.00102

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

APOE5 VARIANT

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1991

- -

Familial type 3 hyperlipoproteinemia;C0036489:Sea-blue histiocyte syndrome;C1843013:Alzheimer disease 3;C1863051:Alzheimer disease 2;C1864205:Age related macular degeneration 1;C2673196:Lipoprotein glomerulopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 05, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2019

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.64

T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

L;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.99

N;N;.;N

REVEL

Uncertain

0.42

Sift

Benign

0.052

T;T;.;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0050

B;.;.;.

Vest4

0.76

MVP

0.90

MPC

0.69

ClinPred

0.011

GERP RS

1.5

Varity_R

0.092

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

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