chr21-25894451-C-T

Position:

• chr21-25894451-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.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

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.2065-2583G>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.2065-2583G>A		intron_variant		1	NM_000484.4	ENSP00000284981.4

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

Gnomad4 AFR AF: 0.858

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.751

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.776

Gnomad4 NFE AF: 0.806

Gnomad4 OTH AF: 0.779

Alfa AF: 0.801 Hom.: 22260

Bravo AF: 0.798

Asia WGS AF: 0.721 AC: 2511 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.32

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: rs1783025; hg19: chr21-27266763;