chr14-73192862-A-C

Position:

• chr14-73192862-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000021.4(PSEN1):​c.767A>C​(p.Tyr256Ser) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y256N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSEN1 NM_000021.4 missense, splice_region
• Scores: Splicing: ADA: 0.6706
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 9.16

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr14-73192861-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2419054.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.767A>C	p.Tyr256Ser	missense_variant, splice_region_variant	7/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.767A>C	p.Tyr256Ser	missense_variant, splice_region_variant	7/12	1	NM_000021.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

-

- -

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	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	.;H;.;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.97
MutPred		0.78		.;Gain of catalytic residue at D257 (P = 5e-04);.;Gain of catalytic residue at D257 (P = 5e-04);.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.58
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

Publications

LitVar

Other links and lift over

dbSNP: rs63751320; hg19: chr14-73659570;