chr14-73170813-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2

The NM_000021.4(PSEN1):c.104G>A(p.Arg35Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00038 in 1,614,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

PSEN1
NM_000021.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 3.90

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a chain Presenilin-1 NTF subunit (size 297) in uniprot entity PSN1_HUMAN there are 186 pathogenic changes around while only 3 benign (98%) 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=0.12319812).

BP6

Variant 14-73170813-G-A is Benign according to our data. Variant chr14-73170813-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98004.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=3, not_provided=1}. Variant chr14-73170813-G-A is described in Lovd as [Benign]. Variant chr14-73170813-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4 link	c.104G>A	p.Arg35Gln	missense_variant	Exon 4 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.104G>A	p.Arg35Gln	missense_variant	Exon 4 of 12	1	NM_000021.4	ENSP00000326366.5		P49768-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251364

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

270

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000480

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000289

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000395

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2024	Variant summary: PSEN1 c.104G>A (p.Arg35Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PSEN1 causing Alzheimer Disease, Type 3, allowing no conclusion about variant significance. c.104G>A has been reported in the literature in individuals affected with Alzheimer Disease, Type 3 without strong evidence for causality and non-segregation has been reported in one family (e.g. Rogaeva_2001, Raux_2005, Guerreiro_2010, Rehker_2017). Experimental evidence evaluating an impact on protein function showed moderate to no effect of this variant on amyloid beta 42/40 pepitide ratios in vitro compared to the WT protein (e.g. Sun_2017, Hsu_2020, Petit_2022). The following publications have been ascertained in the context of this evaluation (PMID: 18667258, 32087291, 35365805, 28985224, 11524469, 27930341). ClinVar contains an entry for this variant (Variation ID: 98004). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	This variant is associated with the following publications: (PMID: 28554858, 16923167, 26159191, 32087291, 30924900, 27930341, 11524469, 23990795, 18667258, 23861362) -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Alzheimer disease 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 12, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Alzheimer disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2024

- -

Dilated cardiomyopathy 1U

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 12, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.010

T;T;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

D;D;T;.;T;D;T;T;.;T;T;T;T;D;T;D;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.4

.;.;.;.;.;.;.;L;.;L;.;.;.;.;.;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.31

N;D;N;N;N;N;N;N;N;N;N;N;N;D;N;D;N

REVEL

Uncertain

0.54

Sift

Benign

0.45

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.41

T;D;T;T;T;T;T;T;T;T;T;T;T;D;T;D;T

Polyphen

0.024, 0.026, 0.0

.;.;.;.;.;.;.;B;B;B;.;.;.;.;B;.;.

Vest4

0.32, 0.33, 0.33, 0.35

MVP

0.92

MPC

0.61

ClinPred

0.017

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.44

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