chr14-73219161-G-C
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000021.4(PSEN1):c.1276G>C(p.Ala426Pro) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PSEN1
NM_000021.4 missense
NM_000021.4 missense
Scores
10
5
1
Clinical Significance
Conservation
PhyloP100: 9.90
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000021.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, PSEN1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
Variant 14-73219161-G-C is Pathogenic according to our data. Variant chr14-73219161-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73219161-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.1276G>C | p.Ala426Pro | missense_variant | 12/12 | ENST00000324501.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN1 | ENST00000324501.10 | c.1276G>C | p.Ala426Pro | missense_variant | 12/12 | 1 | NM_000021.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2022 | Previously reported in individuals with Alzheimer disease (AD); but it is unknown whether these individuals were screened for variants in other genes associated with AD (Poorkaj et al., 1998; Wellington et al., 2016); Published functional studies demonstrate that the variant impairs PSEN1 function (Nelson et al., 2010; Sun et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23990795, 18797263, 19478666, 26756738, 24729694, 36075457, 34918018, 21084313, 27930341, 24698269, 25217249, 26826204, 30045758, 21663966, 20634584, 9521423, 17553989) - |
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3;C3160720:Dilated cardiomyopathy 1U Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 16, 2021 | - - |
Alzheimer disease 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;D;.;.
Vest4
MutPred
0.80
.;Gain of catalytic residue at T421 (P = 0);.;.;.;
MVP
MPC
1.7
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