21-25894451-C-T

Variant names:

• chr21-25894451-C-T
• rs1783025
• NM_000484.4:c.2065-2583G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000484.4(APP):​c.2065-2583G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 152,172 control chromosomes in the GnomAD database, including 49,092 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (49092 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ABeta amyloidosis, Arctic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, dutch type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Iowa type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Italian type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaA21G amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaL34V amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.2065-2583G>A		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.2011-2583G>A		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.2008-2583G>A		intron	N/A	NP_958816.1	P05067-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.2065-2583G>A		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.2008-2583G>A		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.1897-2583G>A		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121968 AN: 152054 Hom.: 49054 Cov.: 33

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.780

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.802 AC: 122058 AN: 152172 Hom.: 49092 Cov.: 33 AF XY: 0.797 AC XY: 59274 AN XY: 74390

African (AFR) AF: 0.858 AC: 35616 AN: 41516

American (AMR) AF: 0.743 AC: 11355 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2608 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3265 AN: 5164

South Asian (SAS) AF: 0.738 AC: 3559 AN: 4820

European-Finnish (FIN) AF: 0.776 AC: 8212 AN: 10578

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.806 AC: 54834 AN: 68018

Other (OTH) AF: 0.779 AC: 1646 AN: 2114

Alfa AF: 0.801 Hom.: 24722

Bravo AF: 0.798

Asia WGS AF: 0.721 AC: 2511 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.32
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1783025; hg19: chr21-27266763;