chr21-25891796-C-T

Position:

chr21-25891796-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000484.4(APP):c.2137G>A(p.Ala713Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

APP
NM_000484.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

APP links:

APP (HGNC:):

APP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a peptide P3(42) (size 25) in uniprot entity A4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000484.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

PP5

Variant 21-25891796-C-T is Pathogenic according to our data. Variant chr21-25891796-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-25891796-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4 linkuse as main transcript	c.2137G>A	p.Ala713Thr	missense_variant	17/18	ENST00000346798.8	NP_000475.1	P05067-1A0A140VJC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 linkuse as main transcript	c.2137G>A	p.Ala713Thr	missense_variant	17/18	1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251384

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000559

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alzheimer disease

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2023	Variant summary: APP c.2137G>A (p.Ala713Thr) results in a non-conservative amino acid change located in the Amyloidogenic glycoprotein, amyloid-beta peptide (IPR013803) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251384 control chromosomes with 24 heterozygotes in GnomAD. c.2137G>A has been reported in the literature in multiple individuals affected with Autosomal dominant Alzheimer Disease and/or cerebrovascular lesion (examples, Carter_1992, Rossi_2004, Armstrong_2004, Bernardi_2009, Moro_2012, Pera_2013, Conidi_2014, Barber_2016, Lanoiselee_2017). Most of patients had a family history of Alzheimer Disease, and the clinical presentation featured with a progressive cognitive decline with a wide range of onset ages (49 to 85 years-old). Particularly, the variant was reported at a homozygous state in 3 patients from a consanguineous family with Alzheimer Disease and cerebrovascular lesion, and the clinical outcome and disease onset were not different from the heterozygous carriers from the same family (Conidi_2014). Meanwhile, multiple asymptomatic carriers were reported, including one 88-years-old woman (example, Carter_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which suggest this variant resulted in a significant increase in the Beta amyloid 42/40 ratio compared with WT in N2A cells via ELISA, the total amount of Beta amyloid was however reduced (Hsu_2020). Such results does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 15488330, 24278680, 19363265, 1303275, 25948718, 32087291, 28350801, 23143229, 23224319, 15365148). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=3, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 21, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APP function (PMID: 29459625). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APP protein function. ClinVar contains an entry for this variant (Variation ID: 18094). This missense change has been observed in individual(s) with Alzheimer's disease and a positive family history of the disorder, although many of these individuals did not have early onset of disease. In addition, it has been reported in the heterozygous state in 2 affected individuals and the homozygous state in 3 affected individuals from a single consanguineous family (PMID: 15365148, 15488330, 19363265, 23224319, 25948718, 26803359, 28350801). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750066, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the APP protein (p.Ala713Thr). -

not provided

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2024	While the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, it is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org), PMID: 1303275, 19363265, 26803359, 29859640, 30279455, 32917274). This variant has been identified in at least one individual with clinical features associated with this gene. This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 29459625, 32087291) -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Primary degenerative dementia of the Alzheimer type, presenile onset

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2019

The p.Ala713Thr variant in APP has been reported in 16 probands with Alzheimer disease and segregated in 8 affected family members (Carter 1992, Rossi 2004, Amstrong 2004, Bernandi 2009, Pera 2013, Conidi 2015, Barber 2016, Lanoiselee 2017, Koriath 2018). In one family with 6 affected individuals, all 3 living affected harbored the variant and 6 of 24 unaffected members (1 over the age of 65) carried the variant (Rossi 2004). In another family the variant was also present in 5 unaffected members (3 over the age of 62) (Carter 1992). In a third family there was one additional affected family member, however, the carrier status was not determined (Amstrong 2004). In 3 additional families the probands presented with late onset Alzheimer disease associated with cerebrovascular lesions. Other family members were reportedly affected with dementia; however their carrier status for the p.Ala713Thr variant was not documented (Bernandi 2009). In another multigenerational family, the variant was found in 5 patients (2 heterozygous and 3 homozygous) and in 6 asymptomatic at risk individuals (Conidi 2015). This variant has also been identified in 21/34414 (0.061%) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 18094). Computational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant exists in a region of the protein where other pathogenic variants cluster and is a known site for protein cleavage. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala713Thr variant is likely pathogenic albeit with reduced and age-related penetrance. ACMG/AMP Criteria applied:PP1_Strong, PM1, PP3. -

Alzheimer disease type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 14, 2004

- -

Cerebral amyloid angiopathy, APP-related

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0101 – Toxic gain of function is a known mechanism of disease in this gene and is associated with cerebral amyloid angiopathy (MIM#605714) and familial Alzheimer disease 1 (MIM#104300) (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Specifically, the p.(Ala713Thr) variant has been reported to have incomplete penetrance as there are unaffected carriers of this variant (PMID: 28350801; gnomAD). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable ages of onset and differences in disease progression have been reported (PMID: 24650794; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (25 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Ala713Val): 13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). The amino acid residue is also a gamma-secretase cleavage site (UniProt). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Ala713Val) has been described as ‘not pathogenic’ in the literature, with no increase in the ABeta42/40 ratio or ABeta42 demonstrated for this variant (PMIDs: 32087291, 31011484). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with mild cognitive impairment, progressive dementia and Alzheimer disease including several large families with Alzheimer disease (PMIDs: 15488330, 15365148, 23143229, 25948718, 28350801, 32908482). It should be noted that this variant was recently classified as a risk factor; however limited justification was provided for the classification (PMID: 32087291). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Injection of human brain extracts from a deceased individual carrying the p.(Ala713Thr) variant into mice resulted in brain amyloidosis with higher ABeta levels detected in the insoluble faction of brain homogenates compared to control mice (PMID: 29459625). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.;.;.;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.3

D;D;D;D;.;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0050

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

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.;D;.

Vest4

0.91

MutPred

0.91

Loss of helix (P = 0.028);.;.;.;.;.;.;.;

MVP

0.99

MPC

1.2

ClinPred

0.64

GERP RS

5.7

Varity_R

0.83

gMVP

0.97

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