14-73171047-T-C

Position:

• chr14-73171047-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000021.4(PSEN1):​c.338T>C​(p.Leu113Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L113Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense, splice_region
• Scores: Splicing: ADA: 0.9475
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 6.03

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]

PSEN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• 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 chr14-73171047-T-A 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). GenCC has associacion of 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, 0.977
• PP5: Variant 14-73171047-T-C is Pathogenic according to our data. Variant chr14-73171047-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73171047-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.338T>C	p.Leu113Pro	missense_variant, splice_region_variant	4/12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.338T>C	p.Leu113Pro	missense_variant, splice_region_variant	4/12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/282660 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -
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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu113 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 15776278), which suggests that this may be a clinically significant amino acid residue. This variant has been reported not to substantially affect PSEN1 protein function (PMID: 17431506, 20634584). This variant has been observed in an individual and a family affected with clinical features of early-onset Alzheimer's disease (PMID: 11094121, Invitae). This gene is also known as PS1 in the literature. ClinVar contains an entry for this variant (Variation ID: 18145). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 113 of the PSEN1 protein (p.Leu113Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Frontotemporal dementia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 28, 2000

- -

Alzheimer disease 3 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;M;.;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;T;D
Polyphen		1.0	.;.;D;D;D;.;.;D;.;.
Vest4		0.99, 0.98, 0.97, 0.97, 0.99
MutPred		0.85		.;.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.030		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: rs63751399; hg19: chr14-73637755;