rs216762

Variant names:

• chr21-25963854-C-T
• rs216762
• NM_000484.4:c.1459-8099G>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.1459-8099G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 151,950 control chromosomes in the GnomAD database, including 22,122 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 0.53 (22122 hom., cov: 31)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.97
• Publications: 7 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):

• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cerebral amyloid angiopathy, APP-related

  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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.1459-8099G>A		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.1459-8099G>A		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.1402-8099G>A		intron	N/A	NP_958816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.1459-8099G>A		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.1402-8099G>A		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.1291-8099G>A		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80017 AN: 151832 Hom.: 22090 Cov.: 31

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.525

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

GnomAD4 genome AF: 0.527 AC: 80105 AN: 151950 Hom.: 22122 Cov.: 31 AF XY: 0.519 AC XY: 38551 AN XY: 74256

African (AFR) AF: 0.673 AC: 27899 AN: 41452

American (AMR) AF: 0.576 AC: 8801 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1705 AN: 3468

East Asian (EAS) AF: 0.301 AC: 1552 AN: 5156

South Asian (SAS) AF: 0.352 AC: 1693 AN: 4804

European-Finnish (FIN) AF: 0.350 AC: 3685 AN: 10528

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.485 AC: 32927 AN: 67950

Other (OTH) AF: 0.525 AC: 1110 AN: 2116

Alfa AF: 0.498 Hom.: 32088

Bravo AF: 0.553

Asia WGS AF: 0.373 AC: 1302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.013
DANN	Benign	0.28
PhyloP100		-3.0
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: rs216762; hg19: chr21-27336168;