14-73173663-A-G

Variant names:

• chr14-73173663-A-G
• rs63750306
• NM_000021.4:c.436A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000021.4(PSEN1):​c.436A>G​(p.Met146Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M146I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.31
• Publications: 2198 publications found

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 Gene-Disease associations (from GenCC):

• Alzheimer disease 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acne inversa, familial, 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1U

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr14-73173665-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18137.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 Alzheimer disease 3, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, acne inversa, familial, 3, Pick disease, behavioral variant of frontotemporal dementia, semantic dementia, early-onset autosomal dominant Alzheimer disease, dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 14-73173663-A-G is Pathogenic according to our data. Variant chr14-73173663-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 18129.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.436A>G	p.Met146Val	missense_variant	Exon 5 of 12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.436A>G	p.Met146Val	missense_variant	Exon 5 of 12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alzheimer disease 3 Pathogenic:2

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Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000021.4(PSEN1):c.436A>G (p.Met146Val) is novel in 1kG All, and gnomAD joint variant frequencies (PM2). There is a small physicochemical difference between methionine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene PSEN1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 3.10. The gene PSEN1 contains 123 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene (PP2). 7 variants within 6 amino acid positions of the variant p.Met146Val have been shown to be pathogenic, while none have been shown to be benign (PM1). The p.Met146Val missense variant is predicted to be damaging by both SIFT and PolyPhen2. Alpha Missense also classifies this variant as pathogenic. The methionine residue at codon 146 of PSEN1 is conserved in all mammalian species. The nucleotide c.436 in PSEN1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates (PP3). The p.Met146Val variant is a missense mutation resulting in an amino acid change which occurs at the same amino acid position as 4 previously classified pathogenic variants (PM5). The variant p.Met146Val has been previously classified as Pathogenic in ClinVar (Variation ID 18129 as of 2025-05-01) with respect to Alzheimer disease 3 with a status of (0 stars) no assertion criteria provided (PP5_STrong). For these reasons, this variant has been classified as Pathogenic. ACMG Criteria: PM2 PM1 PP2 PP3 PP5_Strong PM5 -

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;.;.;D;D;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;L;.;L;.;.;L;.
PhyloP100		7.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;T;T;D;T;T;T
Polyphen		0.99, 0.63, 0.99	.;D;P;D;.;P;.;.
Vest4		0.79, 0.95, 0.90, 0.87, 0.90
MutPred		0.82		.;Gain of catalytic residue at V144 (P = 0.001);.;Gain of catalytic residue at V144 (P = 0.001);Gain of catalytic residue at V144 (P = 0.001);.;Gain of catalytic residue at V144 (P = 0.001);.;
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.83
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750306; hg19: chr14-73640371;