rs63750815
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_000021.4(PSEN1):c.265G>T(p.Val89Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
PSEN1
NM_000021.4 missense
NM_000021.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 10.0
Publications
32 publications found
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 Gene-Disease associations (from GenCC):
- Alzheimer disease 3Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Pick diseaseInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- semantic dementiaInheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- behavioral variant of frontotemporal dementiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset autosomal dominant Alzheimer diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- acne inversa, familial, 3Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathy 1UInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 Alzheimer disease 3, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, acne inversa, familial, 3, Pick disease, behavioral variant of frontotemporal dementia, semantic dementia, early-onset autosomal dominant Alzheimer disease, dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PSEN1 | NM_000021.4 | c.265G>T | p.Val89Leu | missense_variant | Exon 4 of 12 | ENST00000324501.10 | NP_000012.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: not provided
Submissions summary: Other:2
Revision: no classification provided
LINK: link
Submissions by phenotype
not provided Other:1
-
VIB Department of Molecular Genetics, University of Antwerp
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Alzheimer disease 3 Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;D;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;M;.;M;.;.;.;.;M
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;T;T;D;D;D;T;D
Polyphen
1.0, 1.0, 1.0
.;.;.;.;.;.;D;D;D;.;.;.;D;.
Vest4
0.84, 0.84, 0.83, 0.79
MutPred
0.81
.;.;.;Gain of catalytic residue at V94 (P = 0.0017);.;.;Gain of catalytic residue at V94 (P = 0.0017);.;Gain of catalytic residue at V94 (P = 0.0017);.;Gain of catalytic residue at V94 (P = 0.0017);Gain of catalytic residue at V94 (P = 0.0017);.;Gain of catalytic residue at V94 (P = 0.0017);
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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