14-73192712-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000021.4(PSEN1):​c.617G>T​(p.Gly206Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G206S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PSEN1
NM_000021.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 9.83
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 Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000021.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-73192712-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PSEN1. . Gene score misZ 2.1558 (greater than the threshold 3.09). Trascript score misZ 3.0986 (greater than threshold 3.09). GenCC has associacion of gene with acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
Variant 14-73192712-G-T is Pathogenic according to our data. Variant chr14-73192712-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 98051.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73192712-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PSEN1NM_000021.4 linkuse as main transcriptc.617G>T p.Gly206Val missense_variant 7/12 ENST00000324501.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PSEN1ENST00000324501.10 linkuse as main transcriptc.617G>T p.Gly206Val missense_variant 7/121 NM_000021.4 P4P49768-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
not provided, no classification providedliterature onlyVIB Department of Molecular Genetics, University of Antwerp-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;D;.;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.7
.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-8.6
D;D;D;D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.99
MutPred
0.75
.;Gain of catalytic residue at L201 (P = 0);.;Gain of catalytic residue at L201 (P = 0);.;
MVP
0.99
MPC
1.6
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.98
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs63750082; hg19: chr14-73659420; API