rs201290605
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000484.4(APP):c.1458+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 1 hom. )
Consequence
APP
NM_000484.4 intron
NM_000484.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.27
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.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
Variant 21-25975060-C-T is Benign according to our data. Variant chr21-25975060-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585429.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
BS2
?
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APP | NM_000484.4 | c.1458+10G>A | intron_variant | ENST00000346798.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APP | ENST00000346798.8 | c.1458+10G>A | intron_variant | 1 | NM_000484.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000172 AC: 43AN: 250458Hom.: 1 AF XY: 0.000125 AC XY: 17AN XY: 135474
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GnomAD4 exome AF: 0.000226 AC: 331AN: 1461738Hom.: 1 Cov.: 32 AF XY: 0.000193 AC XY: 140AN XY: 727178
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74422
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Alzheimer disease Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 29, 2017 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at