14-73211886-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000021.4(PSEN1):c.1073G>C(p.Arg358Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PSEN1
NM_000021.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.80

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a chain Presenilin-1 CTF12 (size 121) in uniprot entity PSN1_HUMAN there are 64 pathogenic changes around while only 4 benign (94%) in NM_000021.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-73211886-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, PSEN1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4 linkuse as main transcript	c.1073G>C	p.Arg358Pro	missense_variant	10/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10 linkuse as main transcript	c.1073G>C	p.Arg358Pro	missense_variant	10/12	1	NM_000021.4	P4	P49768-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151958

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251456

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000580

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 18, 2016

- -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PSEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 448142). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 358 of the PSEN1 protein (p.Arg358Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

PSEN1: PM5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.35

Cadd

Uncertain

Dann

Benign

0.90

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;N;N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.088

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.011

B;D;B;.

Vest4

0.76

MutPred

0.60

.;Gain of loop (P = 0.0166);.;.;

MVP

0.96

MPC

1.8

ClinPred

0.32

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.60

gMVP

0.97

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