14-73198145-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000021.4(PSEN1):c.868+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,444,742 control chromosomes in the GnomAD database, including 246,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29718 hom., cov: 32)

Exomes 𝑓: 0.58 ( 217223 hom. )

Consequence

PSEN1
NM_000021.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.906

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 14-73198145-G-T is Benign according to our data. Variant chr14-73198145-G-T is described in ClinVar as Benign. ClinVar VariationId is 254714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4 link	c.868+16G>T		intron_variant	Intron 8 of 11	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.868+16G>T		intron_variant	Intron 8 of 11	1	NM_000021.4	ENSP00000326366.5		P49768-1

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93871

AN:

151934

Hom.:

29659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.739

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.654

Gnomad ASJ

AF:

0.598

Gnomad EAS

AF:

0.639

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.609

GnomAD2 exomes

AF:

0.609

AC:

145384

AN:

238688

AF XY:

0.609

show subpopulations

Gnomad AFR exome

AF:

0.747

Gnomad AMR exome

AF:

0.692

Gnomad ASJ exome

AF:

0.586

Gnomad EAS exome

AF:

0.643

Gnomad FIN exome

AF:

0.480

Gnomad NFE exome

AF:

0.552

Gnomad OTH exome

AF:

0.595

GnomAD4 exome

AF:

0.576

AC:

745102

AN:

1292690

Hom.:

217223

Cov.:

AF XY:

0.580

AC XY:

377723

AN XY:

650824

show subpopulations

African (AFR)

AF:

0.742

AC:

22507

AN:

30340

American (AMR)

AF:

0.687

AC:

30088

AN:

43782

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

14586

AN:

24876

East Asian (EAS)

AF:

0.642

AC:

24995

AN:

38912

South Asian (SAS)

AF:

0.730

AC:

59832

AN:

81978

European-Finnish (FIN)

AF:

0.483

AC:

25366

AN:

52554

Middle Eastern (MID)

AF:

0.578

AC:

3114

AN:

5390

European-Non Finnish (NFE)

AF:

0.555

AC:

532624

AN:

960166

Other (OTH)

AF:

0.585

AC:

31990

AN:

54692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

15107

30214

45321

60428

75535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14298

28596

42894

57192

71490

<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:

0.618

AC:

93991

AN:

152052

Hom.:

29718

Cov.:

AF XY:

0.618

AC XY:

45934

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.739

AC:

30660

AN:

41464

American (AMR)

AF:

0.655

AC:

10011

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.598

AC:

2074

AN:

3468

East Asian (EAS)

AF:

0.640

AC:

3308

AN:

5172

South Asian (SAS)

AF:

0.728

AC:

3511

AN:

4820

European-Finnish (FIN)

AF:

0.472

AC:

4984

AN:

10556

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.553

AC:

37580

AN:

67976

Other (OTH)

AF:

0.608

AC:

1284

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1801

3601

5402

7202

9003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.583

Hom.:

35636

Bravo

AF:

0.634

Asia WGS

AF:

0.645

AC:

2241

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18403054, 17719017, 8596269, 28554858) -

Pick disease

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acne inversa, familial, 3

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Frontotemporal dementia

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1U

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alzheimer disease 3

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

-0.91

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over