rs214484

Positions:

• chr21-25881968-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000484.4(APP):​c.2212-197G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 151,930 control chromosomes in the GnomAD database, including 7,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (7048 hom., cov: 31)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.466

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 21-25881968-C-G is Benign according to our data. Variant chr21-25881968-C-G is described in ClinVar as [Benign]. Clinvar id is 1292893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.2212-197G>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.2212-197G>C		intron_variant		1	NM_000484.4	ENSP00000284981

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45088 AN: 151812 Hom.: 7048 Cov.: 31

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.297 AC: 45090 AN: 151930 Hom.: 7048 Cov.: 31 AF XY: 0.292 AC XY: 21712 AN XY: 74244

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.312

Alfa AF: 0.322 Hom.: 1050

Bravo AF: 0.290

Asia WGS AF: 0.257 AC: 894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.72
CADD	Benign	7.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs214484; hg19: chr21-27254279;