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

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PSEN1
NM_000021.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.68
Variant links:
Genes affected
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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
PM4
Nonframeshift variant in NON repetitive region in NM_000021.4. Strenght limited to Supporting due to length of the change: 1aa.
BS2
High AC in GnomAd4 at 18 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSEN1NM_000021.4 linkc.118_120delGAC p.Asp40del conservative_inframe_deletion Exon 4 of 12 ENST00000324501.10 NP_000012.1 P49768-1A0A024R6A3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSEN1ENST00000324501.10 linkc.118_120delGAC p.Asp40del conservative_inframe_deletion Exon 4 of 12 1 NM_000021.4 ENSP00000326366.5 P49768-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251344
Hom.:
0
AF XY:
0.000162
AC XY:
22
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000248
AC:
363
AN:
1461768
Hom.:
0
AF XY:
0.000270
AC XY:
196
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000302
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152332
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000270
Hom.:
0
Bravo
AF:
0.000106
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Uncertain:1
Mar 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Nov 16, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Sep 10, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759538127; hg19: chr14-73637532; API