rs9982544

Positions:

• chr21-25999338-T-C

Variant summary

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

The NM_000484.4(APP):​c.1033+677A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0579 in 152,156 control chromosomes in the GnomAD database, including 835 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 0.058 (835 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.12

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.1033+677A>G		intron_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1033+677A>G		intron_variant		1	NM_000484.4	ENSP00000284981

Frequencies

GnomAD3 genomes AF: 0.0578 AC: 8783 AN: 152038 Hom.: 829 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.0445

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

GnomAD4 genome AF: 0.0579 AC: 8807 AN: 152156 Hom.: 835 Cov.: 32 AF XY: 0.0564 AC XY: 4196 AN XY: 74414

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0471 Hom.: 80

Bravo AF: 0.0659

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
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: rs9982544; hg19: chr21-27371653;