rs2830045

Positions:

• chr21-26086093-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.355+3850T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,154 control chromosomes in the GnomAD database, including 7,322 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 0.28 (7322 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.355+3850T>C		intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.355+3850T>C		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42431 AN: 152036 Hom.: 7322 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.279 AC: 42425 AN: 152154 Hom.: 7322 Cov.: 33 AF XY: 0.281 AC XY: 20891 AN XY: 74392

Gnomad4 AFR AF: 0.0763

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.375

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.309

Alfa AF: 0.311 Hom.: 1679

Bravo AF: 0.261

Asia WGS AF: 0.370 AC: 1285 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.68

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: rs2830045; hg19: chr21-27458409;