rs112965435

Positions:

• chr21-25881780-CAA-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000484.4(APP):​c.2212-11_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 0.000662 in 1,612,422 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (2 hom.)
• Consequence: APP NM_000484.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.0690

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 -9 ACMG points.

• BP6: Variant 21-25881780-CAA-C is Benign according to our data. Variant chr21-25881780-CAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585433.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr21-25881780-CAA-C is described in Lovd as [Likely_benign]. Variant chr21-25881780-CAA-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00187 (284/152182) while in subpopulation AFR AF= 0.00559 (232/41504). AF 95% confidence interval is 0.005. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2212-11_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.2212-11_2212-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152064 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00561

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000793 AC: 199 AN: 250828 Hom.: 0 AF XY: 0.000759 AC XY: 103 AN XY: 135626

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000536 AC: 783 AN: 1460240 Hom.: 2 AF XY: 0.000494 AC XY: 359 AN XY: 726474

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152182 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74398

Gnomad4 AFR AF: 0.00559

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.00228

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2023	Variant summary: APP c.2212-11_2212-10delTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00079 in 250828 control chromosomes. c.2212-11_2212-10delTT has been reported in the literature in an individual affected with Parkinson's disease and Dementia (Shulte_2015). This report does not provide unequivocal conclusions about association of the variant with Alzheimer Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25604855). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Alzheimer disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		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: rs112965435; hg19: chr21-27254091;