rs2830072

Positions:

• chr21-26128343-T-G
• chr21-26128343-T-A

Variant summary

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

The NM_000484.4(APP):​c.58-16197A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 152,122 control chromosomes in the GnomAD database, including 14,271 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 0.39 (14271 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102

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]

LOC124900466 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.58-16197A>C		intron_variant		ENST00000346798.8
LOC124900466	XR_007067829.1	n.8004-5361A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.58-16197A>C		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59451 AN: 152004 Hom.: 14265 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.422

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

GnomAD4 genome AF: 0.391 AC: 59452 AN: 152122 Hom.: 14271 Cov.: 33 AF XY: 0.390 AC XY: 28965 AN XY: 74364

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.424

Alfa AF: 0.436 Hom.: 2447

Bravo AF: 0.366

Asia WGS AF: 0.442 AC: 1535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.71

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: rs2830072; hg19: chr21-27500660;