rs2830000

Positions:

• chr21-25989454-C-A

Variant summary

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

The NM_000484.4(APP):​c.1091-6977G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 151,954 control chromosomes in the GnomAD database, including 7,705 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 0.30 (7705 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100

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]

APP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.1091-6977G>T		intron_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1091-6977G>T		intron_variant		1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45827 AN: 151836 Hom.: 7699 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.302 AC: 45869 AN: 151954 Hom.: 7705 Cov.: 32 AF XY: 0.303 AC XY: 22503 AN XY: 74268

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.267

Alfa AF: 0.248 Hom.: 2635

Bravo AF: 0.308

Asia WGS AF: 0.353 AC: 1225 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.30

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: rs2830000; hg19: chr21-27361768;