Genetic Variant PSEN1:p.Glu318Gly (chr14-73206470-A-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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

Publications

122 publications found

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 Gene-Disease associations (from GenCC):

Alzheimer disease 3
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Pick disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
semantic dementia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
behavioral variant of frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acne inversa, familial, 3
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy 1U
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PSEN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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 early-onset autosomal dominant Alzheimer disease, Pick disease, semantic dementia, Alzheimer disease 3, familial isolated dilated cardiomyopathy, dilated cardiomyopathy, dilated cardiomyopathy 1U, acne inversa, familial, 3, 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 Benign/Likely_benign. ClinVar VariationId is 98094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 passed quality control check.

BS2

High AC in GnomAd4 at 2220 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000021.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	NM_000021.4	MANE Select	c.953A>G	p.Glu318Gly	missense splice_region	Exon 9 of 12	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.941A>G	p.Glu314Gly	missense splice_region	Exon 9 of 12	NP_015557.2	A0A0S2Z4D2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.953A>G	p.Glu318Gly	missense splice_region	Exon 9 of 12	ENSP00000326366.5	P49768-1
PSEN1	ENST00000357710.8	TSL:1	c.941A>G	p.Glu314Gly	missense splice_region	Exon 9 of 12	ENSP00000350342.4	P49768-2
PSEN1	ENST00000394164.5	TSL:1	c.941A>G	p.Glu314Gly	missense splice_region	Exon 9 of 12	ENSP00000377719.1	P49768-2

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

African (AFR)

AF:

0.00225

AC:

AN:

33342

American (AMR)

AF:

0.00657

AC:

294

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

646

AN:

26082

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39632

South Asian (SAS)

AF:

0.00608

AC:

524

AN:

86118

European-Finnish (FIN)

AF:

0.0331

AC:

1767

AN:

53390

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0199

AC:

21998

AN:

1105728

Other (OTH)

AF:

0.0171

AC:

1030

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1115

2229

3344

4458

5573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00296

AC:

123

AN:

41590

American (AMR)

AF:

0.00981

AC:

150

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00559

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1433

AN:

68030

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Alzheimer disease (1)

Alzheimer disease 3 (1)

Dilated cardiomyopathy 1U (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.17

Eigen_PC

Benign

0.011

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0040

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.2

PhyloP100

6.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.48

Sift

Benign

0.14

Sift4G

Benign

0.34

Polyphen

0.0030

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over