rs2070657

Positions:

• chr21-25982704-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000484.4(APP):​c.1091-227A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,126 control chromosomes in the GnomAD database, including 4,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (4913 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.349

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-25982704-T-C is Benign according to our data. Variant chr21-25982704-T-C is described in ClinVar as [Benign]. Clinvar id is 1292634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.1091-227A>G		intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.1091-227A>G		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36721 AN: 152008 Hom.: 4890 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.242 AC: 36775 AN: 152126 Hom.: 4913 Cov.: 32 AF XY: 0.243 AC XY: 18075 AN XY: 74360

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.365

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.218

Alfa AF: 0.204 Hom.: 4490

Bravo AF: 0.255

Asia WGS AF: 0.385 AC: 1334 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.60
DANN	Benign	0.39

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: rs2070657; hg19: chr21-27355017;