rs8132200

Variant names:

• chr21-25997040-T-G
• rs8132200
• NM_000484.4:c.1090+320A>C

Variant summary

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

The NM_000484.4(APP):​c.1090+320A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 347,676 control chromosomes in the GnomAD database, including 13,179 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 0.29 (8124 hom., cov: 33)
  • Exomes 𝑓: 0.21 (5055 hom.)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1090+320A>C		intron_variant	Intron 8 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1090+320A>C		intron_variant	Intron 8 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44089 AN: 152040 Hom.: 8113 Cov.: 33

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.208 AC: 40695 AN: 195518 Hom.: 5055 AF XY: 0.216 AC XY: 22609 AN XY: 104704

African (AFR) AF: 0.507 AC: 3005 AN: 5926

American (AMR) AF: 0.216 AC: 1538 AN: 7136

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 822 AN: 5594

East Asian (EAS) AF: 0.259 AC: 2625 AN: 10150

South Asian (SAS) AF: 0.309 AC: 8560 AN: 27672

European-Finnish (FIN) AF: 0.144 AC: 1321 AN: 9202

Middle Eastern (MID) AF: 0.176 AC: 136 AN: 774

European-Non Finnish (NFE) AF: 0.173 AC: 20538 AN: 118580

Other (OTH) AF: 0.205 AC: 2150 AN: 10484

GnomAD4 genome AF: 0.290 AC: 44126 AN: 152158 Hom.: 8124 Cov.: 33 AF XY: 0.287 AC XY: 21342 AN XY: 74386

African (AFR) AF: 0.528 AC: 21882 AN: 41452

American (AMR) AF: 0.226 AC: 3451 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1430 AN: 5178

South Asian (SAS) AF: 0.321 AC: 1550 AN: 4830

European-Finnish (FIN) AF: 0.165 AC: 1750 AN: 10604

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12744 AN: 68010

Other (OTH) AF: 0.253 AC: 534 AN: 2110

Alfa AF: 0.210 Hom.: 9233

Bravo AF: 0.302

Asia WGS AF: 0.280 AC: 973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.63
PhyloP100		-1.3
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: rs8132200; hg19: chr21-27369355;