rs63750526

chr14-73192832-C-A

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.737C>A(p.Ala246Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,208 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.84

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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, 0.948
• PP5: Variant 14-73192832-C-A is Pathogenic according to our data. Variant chr14-73192832-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73192832-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.737C>A	p.Ala246Glu	missense_variant	7/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.737C>A	p.Ala246Glu	missense_variant	7/12	1	NM_000021.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2022	This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341). -
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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2017

Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. For these reasons, this variant has been classified as Pathogenic. -

Alzheimer disease 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 29, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.98	D;D;D;.;.
Vest4		0.94
MutPred		0.77		.;Gain of catalytic residue at E243 (P = 0.0483);.;Gain of catalytic residue at E243 (P = 0.0483);.;
MVP		0.99
MPC		1.5
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.99

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: rs63750526; hg19: chr14-73659540;