rs140304729

Positions:

chr21-25911855-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000484.4(APP):c.1795G>A(p.Glu599Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000944 in 1,614,164 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 3 hom. )

Consequence

APP
NM_000484.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 5.25

Variant links:

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

APP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01247862).

BP6

Variant 21-25911855-C-T is Benign according to our data. Variant chr21-25911855-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-25911855-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (205/152274) while in subpopulation NFE AF= 0.00116 (79/68018). AF 95% confidence interval is 0.000955. There are 2 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4 linkuse as main transcript	c.1795G>A	p.Glu599Lys	missense_variant	14/18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 linkuse as main transcript	c.1795G>A	p.Glu599Lys	missense_variant	14/18	1	NM_000484.4	ENSP00000284981		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00137

AC:

345

AN:

251480

Hom.:

AF XY:

0.00145

AC XY:

197

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00831

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000902

AC:

1319

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

675

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00818

Gnomad4 NFE exome

AF:

0.000742

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152274

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

133

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	APP: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2017	- -

Alzheimer disease

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Vascular dementia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Myllykangas group, University of Helsinki

Apr 01, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2024

Variant summary: APP c.1795G>A (p.Glu599Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a global frequency of 0.00094 in 1614164 control chromosomes in the gnomAD database, including 5 homozygotes. This variant also at a high frequency among individuals of Finnish descent (subpopulation frequency 0.0087). c.1795G>A has been reported in the literature in the heterozygous state in at least 35/10405 affected individuals with various neurodegenerative conditions including Parkinson's disease, amyloidosis, Alzheimer's disease, dementia, Lewy body disease, vascular dementia, and cognitive/behavioral syndromes (example, Chen_2022, Chyra Kufova_2018, Cruchaga_2012, Geiger_2016, Ghani_2015, Ibanez_2018, Monkare_2021, Nicolas_2018, Perrone_2020, Picillo_2021, Rehker_2017, Salemi_2023, Sassi_2014, Schulte_2015). It has also been reported in 57/27125 control individuals from these studies. A Chi-squared test (Yates correlation, 2-tailed) resulted in a Chi-squared value of 4.398 with 1 degree of freedom (p value=0.036). The calculated odds ratio was 1.60074. These data suggest a possible association of this variant with late-onset neurodegenerative disease. However, the reported phenotypes among affected individuals were not all consistent with APP-related conditions, the number of affected cases and p value are not sufficient to meet current risk allele recommendations (PMID: 38054408), and the early-onset/highly penetrant nature of APP-related Alzheimer's disease conflicts with the lack of pedigree information for this variant. At least one in vitro assay showed an increased ratio of Abeta42 (toxic)/Abeta40 protein in mouse neuroblastoma cells however this does not allow convincing conclusions about the variant effect as the overall Abeta protein levels were below those in wild type controls (example, Hsu_2020). The following publications have been ascertained in the context of this evaluation (PMID: 35861376, 29455155, 22312439, 27312774, 25174650, 32087291, 29692703, 33268848, 30114415, 26242991, 32917274, 33601107, 28985224, 38137339, 25104557, 25604855). ClinVar contains an entry for this variant (Variation ID: 585430). Based on the evidence outlined above, the variant was classified as likely benign. -

APP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;.;.;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.8

N;N;N;N;.;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.015

D;D;D;D;.;D;D;T

Sift4G

Uncertain

0.054

T;T;T;D;D;D;T;D

Polyphen

0.98

D;D;D;D;.;.;D;.

Vest4

0.75

MVP

0.90

MPC

0.94

ClinPred

0.076

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.77

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