14-73170824-AACG-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PM4_SupportingBS2_Supporting
The NM_000021.4(PSEN1):c.118_120delGAC(p.Asp40del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000236 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000021.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.118_120delGAC | p.Asp40del | conservative_inframe_deletion | Exon 4 of 12 | ENST00000324501.10 | NP_000012.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251344Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135878
GnomAD4 exome AF: 0.000248 AC: 363AN: 1461768Hom.: 0 AF XY: 0.000270 AC XY: 196AN XY: 727186
GnomAD4 genome AF: 0.000118 AC: 18AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74500
ClinVar
Submissions by phenotype
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Uncertain:1
This variant, c.118_120del, results in the deletion of 1 amino acid(s) of the PSEN1 protein (p.Asp40del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759538127, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of Alzheimer disease (PMID: 24463146, 32917274, 35949106). ClinVar contains an entry for this variant (Variation ID: 1505666). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PSEN1 function (PMID: 27930341, 32087291). 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. -
not provided Uncertain:1
The PSEN1 c.118_120del; p.Asp40del variant (rs759538127, ClinVar Variation ID: 1505666) is reported in the literature in individuals affected with Alzheimer’s disease (Course 2023, Nygaard 2014, Perrone 2020); however, no family studies were available. This variant is found in the general population with an overall allele frequency of 0.01% (38/282,748 alleles) in the Genome Aggregation Database (v2.1.1). This variant deletes a single aspartic acid residue leaving the rest of the protein in-frame. Functional analyses of the variant protein by gamma-secretase show reduced production of AB42 and AB40 peptides (Sun 2017); however, in mouse N2A cells show an increase in production of AB42 and AB40 peptides (Hsu 2020). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Course MM et al. Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain. 2023 Feb 13;146(2):507-518. PMID: 35949106. Hsu S et al. validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. PMID: 32087291. Nygaard HB et al. A Novel Presenilin 1 Mutation in Early-Onset Alzheimer's Disease With Prominent Frontal Features. Am J Alzheimers Dis Other Demen. 2014 Aug;29(5):433-5. PMID: 24463146. Perrone F et al. Amyloid-ß1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PMID: 32917274. Sun L et al. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aß42 and Aß40 peptides by ?-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. PMID: 27930341 -
PSEN1-related disorder Uncertain:1
The PSEN1 c.118_120delGAC variant is predicted to result in an in-frame deletion (p.Asp40del). This variant has been found in a patient with early onset Alzheimer disease, but no further segregation study was performed (Nygaard et al. 2014. PubMed ID: 24463146). This variant may affect the protein function, but the pathogenicity of the variant has not been elucidated (Sun et al. 2017. PubMed ID: 27930341; Perrone et al. 2020. PubMed ID: 32917274). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at