14-73173587-A-C

Variant names:

• chr14-73173587-A-C
• rs63751272
• NM_000021.4:c.360A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in 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
• Publications: 16 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.

• PS1: Transcript NM_000021.4 (PSEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 VariationId is 98019.Status of the report is criteria_provided_single_submitter, 1 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, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.360A>C	p.Glu120Asp	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.360A>C	p.Glu120Asp	missense_variant	Exon 5 of 12	1	NM_000021.4	ENSP00000326366.5

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
MutationAssessor	Uncertain	2.1	.;.;M;.;M;.;.;M;.
PhyloP100		4.2
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
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs63751272; hg19: chr14-73640295;