rs17125721

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000021.4(PSEN1):c.953A>G(p.Glu318Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0178 in 1,607,260 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 27 hom., cov: 32)

Exomes 𝑓: 0.018 ( 318 hom. )

Consequence

PSEN1
NM_000021.4 missense, splice_region

Scores

Splicing: ADA: 0.06881

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 6.94

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a chain Presenilin-1 CTF subunit (size 168) in uniprot entity PSN1_HUMAN there are 69 pathogenic changes around while only 7 benign (91%) in NM_000021.4

PP2

Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052029192).

BP6

Variant 14-73206470-A-G is Benign according to our data. Variant chr14-73206470-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 98094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73206470-A-G is described in Lovd as [Benign]. Variant chr14-73206470-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2220/152350) while in subpopulation NFE AF = 0.0211 (1433/68030). AF 95% confidence interval is 0.0202. There are 27 homozygotes in GnomAd4. There are 1065 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 2220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4 link	c.953A>G	p.Glu318Gly	missense_variant, splice_region_variant	Exon 9 of 12	ENST00000324501.10	NP_000012.1	P49768-1A0A024R6A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10 link	c.953A>G	p.Glu318Gly	missense_variant, splice_region_variant	Exon 9 of 12	1	NM_000021.4	ENSP00000326366.5		P49768-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2220

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0146

AC:

3664

AN:

250846

AF XY:

0.0150

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0188

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0181

AC:

26363

AN:

1454910

Hom.:

318

Cov.:

AF XY:

0.0178

AC XY:

12876

AN XY:

724256

show subpopulations

Gnomad4 AFR exome

AF:

0.00225

AC:

AN:

33342

Gnomad4 AMR exome

AF:

0.00657

AC:

294

AN:

44716

Gnomad4 ASJ exome

AF:

0.0248

AC:

646

AN:

26082

Gnomad4 EAS exome

AF:

0.0000505

AC:

AN:

39632

Gnomad4 SAS exome

AF:

0.00608

AC:

524

AN:

86118

Gnomad4 FIN exome

AF:

0.0331

AC:

1767

AN:

53390

Gnomad4 NFE exome

AF:

0.0199

AC:

21998

AN:

1105728

Gnomad4 Remaining exome

AF:

0.0171

AC:

1030

AN:

60148

Heterozygous variant carriers

1115

2229

3344

4458

5573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

780

1560

2340

3120

3900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2220

AN:

152350

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1065

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00296

AC:

0.00295744

AN:

0.00295744

Gnomad4 AMR

AF:

0.00981

AC:

0.0098052

AN:

0.0098052

Gnomad4 ASJ

AF:

0.0277

AC:

0.0276657

AN:

0.0276657

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00559

AC:

0.00558775

AN:

0.00558775

Gnomad4 FIN

AF:

0.0322

AC:

0.0321973

AN:

0.0321973

Gnomad4 NFE

AF:

0.0211

AC:

0.0210642

AN:

0.0210642

Gnomad4 OTH

AF:

0.0166

AC:

0.016572

AN:

0.016572

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0122

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0187

AC:

161

ExAC

AF:

0.0145

AC:

1762

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0176

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 22, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10896268, 32087291, 30381075, 28798025, 29177109, 28554858, 27930341, 27535542, 27357204, 27312774, 8773614, 23990795, 10643802, 25333068, 20194882, 19111578, 22906081, 21959359, 21033353, 22810102, 16033913) -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alzheimer disease 3

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dilated cardiomyopathy 1U

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Alzheimer disease

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;D;.;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.011

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

.;T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.2

.;L;.;L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

N;N;N;D;N

REVEL

Uncertain

0.48

Sift

Benign

0.14

T;T;T;D;T

Sift4G

Benign

0.34

T;T;T;T;T

Polyphen

0.0030

B;B;B;.;.

Vest4

0.033

MPC

0.69

ClinPred

0.013

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.21

Mutation Taster

=87/13

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.069

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over