rs2830054

chr21-26103787-G-Tchr21-26103787-G-C

Variant summary

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

The NM_000484.4(APP):c.225+8192C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,920 control chromosomes in the GnomAD database, including 22,194 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 0.51 (22194 hom., cov: 31)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.805

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 (NFE) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.225+8192C>A		intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.225+8192C>A		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78171 AN: 151802 Hom.: 22189 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.540

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

GnomAD4 genome AF: 0.515 AC: 78200 AN: 151920 Hom.: 22194 Cov.: 31 AF XY: 0.517 AC XY: 38404 AN XY: 74244

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.692

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.648

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.541

Alfa AF: 0.620 Hom.: 38244

Bravo AF: 0.491

Asia WGS AF: 0.536 AC: 1863 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	0.034
Dann	Benign	0.56

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: rs2830054; hg19: chr21-27476104;