chr21-26015255-C-T
Variant names:
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_000484.4(APP):c.865+6585G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 126,002 control chromosomes in the GnomAD database, including 30,088 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.74 ( 30088 hom., cov: 32)
Consequence
APP
NM_000484.4 intron
NM_000484.4 intron
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.882
Publications
2 publications found
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]
APP Gene-Disease associations (from GenCC):
- Alzheimer disease type 1Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- cerebral amyloid angiopathy, APP-relatedInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- ABeta amyloidosis, Arctic typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ABeta amyloidosis, dutch typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ABeta amyloidosis, Iowa typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ABeta amyloidosis, Italian typeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ABetaA21G amyloidosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ABetaL34V amyloidosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset autosomal dominant Alzheimer diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APP | NM_000484.4 | c.865+6585G>A | intron_variant | Intron 6 of 17 | ENST00000346798.8 | NP_000475.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.737 AC: 92832AN: 125956Hom.: 30075 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
92832
AN:
125956
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome AF: 0.737 AC: 92866AN: 126002Hom.: 30088 Cov.: 32 AF XY: 0.734 AC XY: 45013AN XY: 61356 show subpopulations
GnomAD4 genome
AF:
AC:
92866
AN:
126002
Hom.:
Cov.:
32
AF XY:
AC XY:
45013
AN XY:
61356
show subpopulations
African (AFR)
AF:
AC:
16695
AN:
26818
American (AMR)
AF:
AC:
8340
AN:
12018
Ashkenazi Jewish (ASJ)
AF:
AC:
2589
AN:
3268
East Asian (EAS)
AF:
AC:
2981
AN:
4252
South Asian (SAS)
AF:
AC:
2621
AN:
3814
European-Finnish (FIN)
AF:
AC:
7141
AN:
9460
Middle Eastern (MID)
AF:
AC:
201
AN:
264
European-Non Finnish (NFE)
AF:
AC:
50180
AN:
63406
Other (OTH)
AF:
AC:
1369
AN:
1822
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1709
3418
5127
6836
8545
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Genome Hom
Variant carriers
0
766
1532
2298
3064
3830
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
1930
AN:
3426
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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