rs2014146

Positions:

• chr21-25962708-A-G

Variant summary

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

The NM_000484.4(APP):​c.1459-6953T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 152,134 control chromosomes in the GnomAD database, including 17,018 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 0.45 (17018 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.1459-6953T>C		intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.1459-6953T>C		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68732 AN: 152016 Hom.: 16988 Cov.: 33

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.452 AC: 68817 AN: 152134 Hom.: 17018 Cov.: 33 AF XY: 0.445 AC XY: 33123 AN XY: 74378

Gnomad4 AFR AF: 0.653

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.453

Alfa AF: 0.387 Hom.: 22285

Bravo AF: 0.478

Asia WGS AF: 0.329 AC: 1146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.35

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: rs2014146; hg19: chr21-27335022;