14-73170832-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000021.4(PSEN1):c.123A>T(p.Arg41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0250

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Presenilin-1 NTF subunit (size 297) in uniprot entity PSN1_HUMAN there are 288 pathogenic changes around while only 8 benign (97%) in NM_000021.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PSEN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.26579523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.123A>T	p.Arg41Ser	missense_variant	4/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.123A>T	p.Arg41Ser	missense_variant	4/12	1	NM_000021.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 06, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PSEN1 protein function. This missense change has been observed in individual(s) with early-onset Parkinsonism (PMID: 32590294). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 41 of the PSEN1 protein (p.Arg41Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.013	T;T;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;T;T;.;T;T;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N;D;N;N;N;N;N;N;N;N;N;N;N;D;N;D;N
REVEL	Uncertain	0.63
Sift	Benign	0.080	T;D;D;D;D;T;D;T;T;T;T;T;D;D;T;D;T
Sift4G	Benign	0.30	T;D;T;T;D;T;T;D;T;T;T;D;D;D;T;D;T
Polyphen		0.76, 0.0060, 0.16	.;.;.;.;.;.;.;P;B;B;.;.;.;.;B;.;.
Vest4		0.39, 0.41, 0.40, 0.43
MutPred		0.20		.;.;.;.;Gain of phosphorylation at R41 (P = 0.0202);.;.;Gain of phosphorylation at R41 (P = 0.0202);.;Gain of phosphorylation at R41 (P = 0.0202);.;Gain of phosphorylation at R41 (P = 0.0202);Gain of phosphorylation at R41 (P = 0.0202);.;.;.;Gain of phosphorylation at R41 (P = 0.0202);
MVP		0.92
MPC		0.60
ClinPred		0.099	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.64

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

Other links and lift over

dbSNP: rs997923176; hg19: chr14-73637540;