rs3025786

chr14-73198010-T-C

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.770-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,426,226 control chromosomes in the GnomAD database, including 1,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (138 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1517 hom.)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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=-0.81).
• BP6: Variant 14-73198010-T-C is Benign according to our data. Variant chr14-73198010-T-C is described in ClinVar as [Benign]. Clinvar id is 1280880.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73198010-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.770-21T>C		intron_variant		ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.770-21T>C		intron_variant		1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5427 AN: 152198 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.00907

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0414

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0353 AC: 8593 AN: 243740 Hom.: 217 AF XY: 0.0360 AC XY: 4742 AN XY: 131776

Gnomad AFR exome AF: 0.00704

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.000386

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0447 AC: 56986 AN: 1273910 Hom.: 1517 Cov.: 18 AF XY: 0.0443 AC XY: 28468 AN XY: 643116

Gnomad4 AFR exome AF: 0.00759

Gnomad4 AMR exome AF: 0.0297

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.000180

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0288

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0433

GnomAD4 genome AF: 0.0356 AC: 5420 AN: 152316 Hom.: 138 Cov.: 32 AF XY: 0.0342 AC XY: 2544 AN XY: 74484

Gnomad4 AFR AF: 0.00904

Gnomad4 AMR AF: 0.0413

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0457 Hom.: 52

Bravo AF: 0.0367

Asia WGS AF: 0.0110 AC: 39 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

Mar 12, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.4
Dann	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs3025786; hg19: chr14-73664718;