rs63750847

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM5BP4_StrongBP6_ModerateBS2

The NM_000484.4(APP):c.2017G>A(p.Ala673Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A673G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

APP
NM_000484.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 2.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a helix (size 2) in uniprot entity A4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000484.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-25897619-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.015611917).

BP6

Variant 21-25897620-C-T is Benign according to our data. Variant chr21-25897620-C-T is described in ClinVar as [Benign]. Clinvar id is 37145.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.2017G>A	p.Ala673Thr	missense_variant	Exon 16 of 18	ENST00000346798.8	NP_000475.1	P05067-1A0A140VJC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 link	c.2017G>A	p.Ala673Thr	missense_variant	Exon 16 of 18	1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000446

AC:

112

AN:

251392

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00345

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000283

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alzheimer disease, protection against

Benign:1

Aug 02, 2012

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Alzheimer disease

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.17

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.070

MetaRNN

Benign

0.016

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

MetaSVM

Uncertain

0.095

MutationAssessor

Benign

0.46

N;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.65

N;N;N;N;.;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.20

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

Sift4G

Benign

0.57

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

Polyphen

0.13

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

Vest4

0.39

MVP

0.80

MPC

0.41

ClinPred

0.044

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.80

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