rs140304729

Variant names:

• chr21-25911855-C-T
• rs140304729
• NM_000484.4:c.1795G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 5.25
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ABeta amyloidosis, Arctic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, dutch type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Iowa type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Italian type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaA21G amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaL34V amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 585430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1795G>A	p.Glu599Lys	missense_variant	Exon 14 of 18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1795G>A	p.Glu599Lys	missense_variant	Exon 14 of 18	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152156 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.00137 AC: 345 AN: 251480 AF XY: 0.00145

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 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.: 3 Cov.: 31 AF XY: 0.000928 AC XY: 675 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00818 AC: 437 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000742 AC: 825 AN: 1112008

Other (OTH) AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152274 Hom.: 2 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74456

African (AFR) AF: 0.000120 AC: 5 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APP: PP3, BS1, BS2 -

Alzheimer disease Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vascular dementia Uncertain:1

Apr 01, 2020

Myllykangas group, University of Helsinki

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Benign:1

Jun 12, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 31, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;M
PhyloP100		5.3
PrimateAI	Pathogenic	0.84	D
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	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.77
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs140304729; hg19: chr21-27284167; COSMIC: COSV60995793;