rs214488

Variant names:

• chr21-25915612-G-A
• rs214488
• NM_000484.4:c.1688-3650C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-25915612-G-A
• chr21-25915612-G-T

Variant summary

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

The NM_000484.4(APP):​c.1688-3650C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 152,194 control chromosomes in the GnomAD database, including 33,667 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 0.62 (33667 hom., cov: 35)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173

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 (NFE) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1688-3650C>T		intron_variant	Intron 13 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1688-3650C>T		intron_variant	Intron 13 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94253 AN: 152076 Hom.: 33665 Cov.: 35

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.666

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

GnomAD4 genome AF: 0.619 AC: 94261 AN: 152194 Hom.: 33667 Cov.: 35 AF XY: 0.616 AC XY: 45832 AN XY: 74420

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.653

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.810

Gnomad4 OTH AF: 0.663

Alfa AF: 0.779 Hom.: 92740

Bravo AF: 0.592

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.33

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: rs214488; hg19: chr21-27287924;