rs2830038

Positions:

• chr21-26070280-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.356-16932T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,048 control chromosomes in the GnomAD database, including 17,588 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 0.46 (17588 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.356-16932T>C		intron_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.356-16932T>C		intron_variant		1	NM_000484.4	ENSP00000284981

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69978 AN: 151930 Hom.: 17561 Cov.: 32

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.461 AC: 70059 AN: 152048 Hom.: 17588 Cov.: 32 AF XY: 0.463 AC XY: 34382 AN XY: 74314

Gnomad4 AFR AF: 0.652

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.505

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.420

Alfa AF: 0.371 Hom.: 21497

Bravo AF: 0.480

Asia WGS AF: 0.476 AC: 1656 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.27

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: rs2830038; hg19: chr21-27442596;