Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate
The NM_000021.4(PSEN1):c.73A>G(p.Thr25Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
PSEN1 (HGNC:9508): (presenilin 1) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
In a chain Presenilin-1 NTF subunit (size 297) in uniprot entity PSN1_HUMAN there are 186 pathogenic changes around while only 3 benign (98%) in NM_000021.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
BP4
Computational evidence support a benign effect (MetaRNN=0.13505918).
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 25 of the PSEN1 protein (p.Thr25Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PSEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PSEN1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);Loss of phosphorylation at T25 (P = 0.0384);