rs214260

Positions:

• chr14-73195921-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000021.4(PSEN1):​c.770-2110C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,100 control chromosomes in the GnomAD database, including 3,527 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3527 hom., cov: 32)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.770-2110C>T		intron_variant		ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.770-2110C>T		intron_variant		1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31413 AN: 151982 Hom.: 3507 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.183

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.207 AC: 31487 AN: 152100 Hom.: 3527 Cov.: 32 AF XY: 0.204 AC XY: 15139 AN XY: 74364

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.0721

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.181

Alfa AF: 0.178 Hom.: 4930

Bravo AF: 0.215

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs214260; hg19: chr14-73662629;