rs396969

Positions:

• chr21-25908865-A-G

Variant summary

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

The ENST00000346798.8(APP):​c.1909+2876T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 152,198 control chromosomes in the GnomAD database, including 63,261 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 0.91 (63261 hom., cov: 32)
• Consequence: APP ENST00000346798.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00900

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.1909+2876T>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.1909+2876T>C		intron_variant		1	NM_000484.4	ENSP00000284981

Frequencies

GnomAD3 genomes AF: 0.911 AC: 138620 AN: 152080 Hom.: 63226 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.905

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

GnomAD4 genome AF: 0.911 AC: 138709 AN: 152198 Hom.: 63261 Cov.: 32 AF XY: 0.909 AC XY: 67644 AN XY: 74408

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.899

Gnomad4 NFE AF: 0.923

Gnomad4 OTH AF: 0.905

Alfa AF: 0.917 Hom.: 29134

Bravo AF: 0.912

Asia WGS AF: 0.882 AC: 3068 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.98
DANN	Benign	0.33

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: rs396969; hg19: chr21-27281177;