14-73198145-G-T

Position:

chr14-73198145-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id is 254714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73198145-G-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4 linkuse as main transcript	c.868+16G>T		intron_variant		ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10 linkuse as main transcript	c.868+16G>T		intron_variant		1	NM_000021.4	ENSP00000326366	P4	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

GnomAD3 exomes

AF:

0.609

AC:

145384

AN:

238688

Hom.:

44825

AF XY:

0.609

AC XY:

78552

AN XY:

128932

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 SAS exome

AF:

0.731

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

Gnomad4 AFR exome

AF:

0.742

Gnomad4 AMR exome

AF:

0.687

Gnomad4 ASJ exome

AF:

0.586

Gnomad4 EAS exome

AF:

0.642

Gnomad4 SAS exome

AF:

0.730

Gnomad4 FIN exome

AF:

0.483

Gnomad4 NFE exome

AF:

0.555

Gnomad4 OTH exome

AF:

0.585

GnomAD4 genome

AF:

0.618

AC:

93991

AN:

152052

Hom.:

29718

Cov.:

AF XY:

0.618

AC XY:

45934

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.739

Gnomad4 AMR

AF:

0.655

Gnomad4 ASJ

AF:

0.598

Gnomad4 EAS

AF:

0.640

Gnomad4 SAS

AF:

0.728

Gnomad4 FIN

AF:

0.472

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.608

Alfa

AF:

0.575

Hom.:

27623

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2018	This variant is associated with the following publications: (PMID: 18403054, 17719017, 8596269, 28554858) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pick disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Acne inversa, familial, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Frontotemporal dementia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dilated cardiomyopathy 1U

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Alzheimer disease 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.65

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

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