Mutations

APP A479S

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25975093 G>T
Position: (GRCh37/hg19):Chr21:27347406 G>T
dbSNP ID: rs143794560
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to TCT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 11

Findings

This variant was detected in a control individual in a study assessing 72 AD cases and 58 controls (Frigerio et al., 2015). There was no family history of dementia. The age of the mutation carrier was not reported, nor were details regarding his or her cognitive health. Classification as a control was based on a lack of significant AD pathology in the brain. 

This variant was found in the gnomAD variant database at a frequency of 0.00003895, with an allele count of 11 (gnomAD v2.1.1, Oct 2021). All 11 alleles were found in non-Finnish Europeans. 

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type APP, resulting in a similar  Aβ42/Aβ40 ratio (Hsu et al., 2020). Consistently, the variant was predicted benign by one in silico algorithm, PolyPhen-2. However, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 15 Mar 2022

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References

Paper Citations

  1. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Other Citations

  1. Frigerio et al., 2015

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

Alzpedia

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