rs165935

Positions:

• chr14-73220436-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000021.4(PSEN1):​c.*1147C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,500 control chromosomes in the GnomAD database, including 29,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29577 hom., cov: 32)
  • Exomes 𝑓: 0.52 (55 hom.)
• Consequence: PSEN1 NM_000021.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.852

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]

PSEN1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-73220436-C-T is Benign according to our data. Variant chr14-73220436-C-T is described in ClinVar as [Benign]. Clinvar id is 313962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.*1147C>T		3_prime_UTR_variant	12/12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.*1147C>T		3_prime_UTR_variant	12/12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93741 AN: 151962 Hom.: 29521 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.524 AC: 220 AN: 420 Hom.: 55 Cov.: 0 AF XY: 0.516 AC XY: 131 AN XY: 254

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.617 AC: 93858 AN: 152080 Hom.: 29577 Cov.: 32 AF XY: 0.618 AC XY: 45913 AN XY: 74346

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.606

Alfa AF: 0.584 Hom.: 11966

Bravo AF: 0.631

Asia WGS AF: 0.650 AC: 2259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Dilated cardiomyopathy 1U Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alzheimer disease 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.65
DANN	Benign	0.28

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: rs165935; hg19: chr14-73687144;