rs63751272

chr14-73173587-A-Cchr14-73173587-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000021.4(PSEN1):c.360A>C(p.Glu120Asp) variant causes a missense change. 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 Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E120K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18

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 14 ACMG points.

• PS1: Transcript NM_000021.4 (PSEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 18135
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr14-73173585-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98019.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PSEN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 14-73173587-A-C is Pathogenic according to our data. Variant chr14-73173587-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.360A>C	p.Glu120Asp	missense_variant	5/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.360A>C	p.Glu120Asp	missense_variant	5/12	1	NM_000021.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;.;D;D;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N;N;N;N;N;D;N;N;N
REVEL	Pathogenic	0.90
Sift	Benign	0.034	D;D;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.47, 1.0	.;.;D;P;D;.;P;.;.
Vest4		0.72, 0.96, 0.89, 0.87, 0.84
MutPred		0.78		.;.;Gain of catalytic residue at D121 (P = 0.0295);.;Gain of catalytic residue at D121 (P = 0.0295);Gain of catalytic residue at D121 (P = 0.0295);.;Gain of catalytic residue at D121 (P = 0.0295);.;
MVP		0.98
MPC		1.4
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63751272; hg19: chr14-73640295;