rs8132200

Positions:

• chr21-25997040-T-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.1090+320A>C		intron_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1090+320A>C		intron_variant		1	NM_000484.4	ENSP00000284981

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

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.205

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

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.253

Alfa AF: 0.200 Hom.: 5559

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

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: rs8132200; hg19: chr21-27369355;