rs753046287

Positions:

• chr21-25881780-CAAG-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000484.4(APP):​c.2212-12_2212-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,612,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: APP NM_000484.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.435

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.

• BP6: Variant 21-25881780-CAAG-C is Benign according to our data. Variant chr21-25881780-CAAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 453313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-25881780-CAAG-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2212-12_2212-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.2212-12_2212-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 250828 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135626

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000329

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1460238 Hom.: 0 AF XY: 0.000187 AC XY: 136 AN XY: 726474

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74398

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

APP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Alzheimer disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753046287; hg19: chr21-27254091;