rs63750973

chr21-25891792-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000484.4(APP):c.2141C>T(p.Thr714Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T714A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000484.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-25891793-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 18102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 21-25891792-G-A is Pathogenic according to our data. Variant chr21-25891792-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18100.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-25891792-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2141C>T	p.Thr714Ile	missense_variant	17/18	ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.2141C>T	p.Thr714Ile	missense_variant	17/18	1	NM_000484.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alzheimer disease type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 25, 2005

- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.089	T;D;D;T;.;T;T;T
Sift4G	Uncertain	0.0020	D;D;D;T;T;T;D;D
Polyphen		1.0	D;D;D;D;.;.;D;.
Vest4		0.85
MutPred		0.60		Gain of helix (P = 0.0854);.;.;.;.;.;.;.;
MVP		1.0
MPC		1.3
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.94

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

Other links and lift over

dbSNP: rs63750973; hg19: chr21-27264104;