rs2830019

Variant names:

• chr21-26030497-T-C
• rs2830019
• NM_000484.4:c.663-8455A>G

Variant summary

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

The NM_000484.4(APP):​c.663-8455A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,222 control chromosomes in the GnomAD database, including 1,270 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 0.10 (1270 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751

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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.663-8455A>G		intron_variant	Intron 5 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.663-8455A>G		intron_variant	Intron 5 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15693 AN: 152102 Hom.: 1259 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0836

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

GnomAD4 genome AF: 0.103 AC: 15730 AN: 152222 Hom.: 1270 Cov.: 32 AF XY: 0.109 AC XY: 8113 AN XY: 74424

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0860

Alfa AF: 0.0784 Hom.: 88

Bravo AF: 0.117

Asia WGS AF: 0.218 AC: 757 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.7
DANN	Benign	0.77

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: rs2830019; hg19: chr21-27402812;