21-26063209-C-T

Position:

• chr21-26063209-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000484.4(APP):​c.356-9861G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 151,994 control chromosomes in the GnomAD database, including 2,775 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 0.17 (2775 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.289

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.356-9861G>A		intron_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.356-9861G>A		intron_variant		1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25831 AN: 151876 Hom.: 2762 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.170 AC: 25844 AN: 151994 Hom.: 2775 Cov.: 32 AF XY: 0.173 AC XY: 12843 AN XY: 74282

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.167

Alfa AF: 0.186 Hom.: 1680

Bravo AF: 0.164

Asia WGS AF: 0.191 AC: 664 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.80

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: rs2830036; hg19: chr21-27435525;