rs63750800

Positions:

• chr14-73173585-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000021.4(PSEN1):​c.358G>A​(p.Glu120Lys) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E120D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 10.0

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 15 ACMG points.

• PS1: Transcript NM_000021.4 (PSEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Lumenal (size 28) in uniprot entity PSN1_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) 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 chr14-73173587-A-T is described in Lovd as [Pathogenic].
• 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). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. GenCC has associacion of the 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, 0.941
• PP5: Variant 14-73173585-G-A is Pathogenic according to our data. Variant chr14-73173585-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98019.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73173585-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.358G>A	p.Glu120Lys	missense_variant	5/12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.358G>A	p.Glu120Lys	missense_variant	5/12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 13, 2018	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;D;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;.;M;.;M;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.061	T;T;D;T;T;D;T;T;T
Sift4G	Benign	0.068	T;D;D;T;T;D;T;T;T
Polyphen		1.0, 0.92, 1.0	.;.;D;P;D;.;P;.;.
Vest4		0.90, 0.99, 0.98, 0.97, 0.97
MutPred		0.79		.;.;Gain of methylation at E120 (P = 0.0062);.;Gain of methylation at E120 (P = 0.0062);Gain of methylation at E120 (P = 0.0062);.;Gain of methylation at E120 (P = 0.0062);.;
MVP		0.99
MPC		1.5
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.59
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

Other links and lift over

dbSNP: rs63750800; hg19: chr14-73640293;