chr21-26054932-G-T

Variant names:

• chr21-26054932-G-T
• rs2830028
• NM_000484.4:c.356-1584C>A

Variant summary

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

The NM_000484.4(APP):​c.356-1584C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 151,792 control chromosomes in the GnomAD database, including 8,815 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 0.32 (8815 hom., cov: 30)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.58

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.356-1584C>A		intron_variant	Intron 3 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.356-1584C>A		intron_variant	Intron 3 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48409 AN: 151674 Hom.: 8789 Cov.: 30

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.319 AC: 48485 AN: 151792 Hom.: 8815 Cov.: 30 AF XY: 0.315 AC XY: 23348 AN XY: 74144

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.286

Alfa AF: 0.246 Hom.: 5188

Bravo AF: 0.337

Asia WGS AF: 0.226 AC: 785 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	0.060
DANN	Benign	0.63

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: rs2830028; hg19: chr21-27427248;