chr21-25965985-T-A
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -3 classification points (ACMG Germline Pathogenicity v2019): 1P and 4B. PM2_SupportingBP4_Strong
The NM_000484.4(APP):c.1458+9085A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000132 (AC=2) in the gnomAD database across 152,008 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Consequence
APP
NM_000484.4 intron
NM_000484.4 intron
Scores
3
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.771
Publications
7 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):
- cerebral amyloid angiopathy, APP-relatedInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
- Alzheimer disease type 1Inheritance: 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
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_000484.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript
Our verdict: Likely_benign. The variant received -3 points.
PM2
Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
BP4
Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated classification assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APP | TSL:1 MANE Select | c.1458+9085A>T | intron | N/A | ENSP00000284981.4 | P05067-1 | |||
| APP | TSL:1 | c.1401+9085A>T | intron | N/A | ENSP00000350578.3 | P05067-8 | |||
| APP | TSL:1 | c.1290+9085A>T | intron | N/A | ENSP00000398879.2 | E9PG40 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152008
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 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74238 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
152008
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74238
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41380
American (AMR)
AF:
AC:
1
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5198
South Asian (SAS)
AF:
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
AC:
0
AN:
10570
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67988
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
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
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs4175 ;
hg19: chr21-27338298;