rs112965435
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
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
NM_000484.4 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 284AN: 152064Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000793 AC: 199AN: 250828Hom.: 0 AF XY: 0.000759 AC XY: 103AN XY: 135626
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GnomAD4 exome AF: 0.000536 AC: 783AN: 1460240Hom.: 2 AF XY: 0.000494 AC XY: 359AN XY: 726474
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GnomAD4 genome ? AF: 0.00187 AC: 284AN: 152182Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138AN XY: 74398
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
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:1Benign: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
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Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 10
Find out detailed SpliceAI scores and Pangolin per-transcript scores at