chr14-73206470-A-G

Position:

chr14-73206470-A-G

Variant summary

Our verdict is Benign. Variant got -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:

PSEN1 (HGNC:):

PSEN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a chain Presenilin-1 CTF subunit (size 168) in uniprot entity PSN1_HUMAN there are 39 pathogenic changes around while only 3 benign (93%) in NM_000021.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PSEN1. . Gene score misZ 2.1558 (greater than the threshold 3.09). Trascript score misZ 3.0986 (greater than threshold 3.09). GenCC has associacion of gene with 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4 linkuse as main transcript	c.953A>G	p.Glu318Gly	missense_variant, splice_region_variant	9/12	ENST00000324501.10	NP_000012.1	P49768-1A0A024R6A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10 linkuse as main transcript	c.953A>G	p.Glu318Gly	missense_variant, splice_region_variant	9/12	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

GnomAD3 exomes

AF:

0.0146

AC:

3664

AN:

250846

Hom.:

AF XY:

0.0150

AC XY:

2036

AN XY:

135626

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 SAS exome

AF:

0.00615

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

Gnomad4 AMR exome

AF:

0.00657

Gnomad4 ASJ exome

AF:

0.0248

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00608

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0171

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

Gnomad4 AMR

AF:

0.00981

Gnomad4 ASJ

AF:

0.0277

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0322

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0180

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2017	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Jan 31, 2024

- -

Alzheimer disease 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Dilated cardiomyopathy 1U

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 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

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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

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