14-73170486-A-G

Position:

• chr14-73170486-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000021.4(PSEN1):​c.88-311A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 152,356 control chromosomes in the GnomAD database, including 44 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 0.015 (44 hom., cov: 32)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.116

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=-0.86).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (2228/152356) while in subpopulation AFR AF= 0.0482 (2004/41582). AF 95% confidence interval is 0.0464. There are 44 homozygotes in gnomad4. There are 1067 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.88-311A>G		intron_variant		ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.88-311A>G		intron_variant		1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2226 AN: 152238 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0144

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

GnomAD4 genome AF: 0.0146 AC: 2228 AN: 152356 Hom.: 44 Cov.: 32 AF XY: 0.0143 AC XY: 1067 AN XY: 74508

Gnomad4 AFR AF: 0.0482

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00275 Hom.: 0

Bravo AF: 0.0161

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.73
DANN	Benign	0.56

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: rs362354; hg19: chr14-73637194;