14-73170824-AACG-A

Variant names:

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]

PSEN1 links:

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
PSEN1	NM_000021.4 link	c.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
PSEN1	ENST00000324501.10 link	c.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:

AN:

152214

Hom.:

Cov.:

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:

AN:

251344

Hom.:

AF XY:

0.000162

AC XY:

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.:

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:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

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.:

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 Alzheimerâ€™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-ÃŸ1-43 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 AÃŸ42 and AÃŸ40 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over