rs1800839

chr14-73136423-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000557356.5(PSEN1):c.-161C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 152,976 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (324 hom., cov: 33)
  • Exomes 𝑓: 0.054 (0 hom.)
• Consequence: PSEN1 ENST00000557356.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.71

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-73136423-C-T is Benign according to our data. Variant chr14-73136423-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	XM_047431601.1	c.-161C>T		5_prime_UTR_variant	1/12
PSEN1	XM_047431602.1	c.-161C>T		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000557356.5	c.-161C>T		5_prime_UTR_variant	1/5	4
PSEN1	ENST00000357710.8			upstream_gene_variant		1		A1
PSEN1	ENST00000555386.6			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8534 AN: 152196 Hom.: 324 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.0522

GnomAD4 exome AF: 0.0544 AC: 36 AN: 662 Hom.: 0 Cov.: 0 AF XY: 0.0482 AC XY: 21 AN XY: 436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0461

Gnomad4 NFE exome AF: 0.0722

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.0560 AC: 8533 AN: 152314 Hom.: 324 Cov.: 33 AF XY: 0.0533 AC XY: 3968 AN XY: 74478

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.00869

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.0886

Gnomad4 OTH AF: 0.0517

Alfa AF: 0.0738 Hom.: 137

Bravo AF: 0.0532

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Early-onset autosomal dominant Alzheimer disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.81

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800839; hg19: chr14-73603131;