rs63751144

Variant names:

• chr14-73186892-C-A
• rs63751144
• NM_000021.4:c.520C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000021.4(PSEN1):​c.520C>A​(p.Leu174Met) 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 ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L174R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.56

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 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 22) in uniprot entity PSN1_HUMAN there are 19 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 chr14-73186893-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 14-73186892-C-A is Pathogenic according to our data. Variant chr14-73186892-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18147.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-73186892-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.520C>A	p.Leu174Met	missense_variant	Exon 6 of 12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.520C>A	p.Leu174Met	missense_variant	Exon 6 of 12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alzheimer disease 3 Pathogenic:1

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

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VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.6	.;H;.;H;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.94
MutPred		0.77		.;Gain of catalytic residue at S169 (P = 2e-04);.;Gain of catalytic residue at S169 (P = 2e-04);.;
MVP		0.96
MPC		1.4
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.84

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: rs63751144; hg19: chr14-73653600;