rs63751223

chr14-73219161-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.96
MutPred		0.80		.;Gain of catalytic residue at T421 (P = 0);.;.;.;
MVP		0.99
MPC		1.7
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs63751223; hg19: chr14-73685869;