NM_000484.4:c.1795G>A
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
Consequence
NM_000484.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
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
Frequencies
GnomAD3 genomes AF: 0.00135 AC: 205AN: 152156Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00137 AC: 345AN: 251480Hom.: 0 AF XY: 0.00145 AC XY: 197AN XY: 135916
GnomAD4 exome AF: 0.000902 AC: 1319AN: 1461890Hom.: 3 Cov.: 31 AF XY: 0.000928 AC XY: 675AN XY: 727246
GnomAD4 genome AF: 0.00135 AC: 205AN: 152274Hom.: 2 Cov.: 32 AF XY: 0.00179 AC XY: 133AN XY: 74456
ClinVar
Submissions by phenotype
not provided Benign:2
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APP: PP3, BS1, BS2 -
Alzheimer disease Benign:2
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. -
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Vascular dementia Uncertain:1
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not specified Benign:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at