chr14-73148358-G-A

Position:

• chr14-73148358-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000021.4(PSEN1):​c.87+252G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 152,182 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.039 (317 hom., cov: 32)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00800

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-73148358-G-A is Benign according to our data. Variant chr14-73148358-G-A is described in ClinVar as [Benign]. Clinvar id is 1251131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.87+252G>A		intron_variant		ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.87+252G>A		intron_variant		1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5894 AN: 152064 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.0310

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

GnomAD4 genome AF: 0.0389 AC: 5923 AN: 152182 Hom.: 317 Cov.: 32 AF XY: 0.0392 AC XY: 2914 AN XY: 74406

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.0492

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.00749 Hom.: 10

Bravo AF: 0.0429

Asia WGS AF: 0.0450 AC: 155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.2
DANN	Benign	0.44

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: rs34623110; hg19: chr14-73615066;