chr21-25982704-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000484.4(APP):​c.1091-227A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,126 control chromosomes in the GnomAD database, including 4,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.24 ( 4913 hom., cov: 32)

Consequence

APP
NM_000484.4 intron

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.349
Variant links:
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 21-25982704-T-C is Benign according to our data. Variant chr21-25982704-T-C is described in ClinVar as [Benign]. Clinvar id is 1292634.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APPNM_000484.4 linkuse as main transcriptc.1091-227A>G intron_variant ENST00000346798.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APPENST00000346798.8 linkuse as main transcriptc.1091-227A>G intron_variant 1 NM_000484.4 P05067-1

Frequencies

GnomAD3 genomes
AF:
0.242
AC:
36721
AN:
152008
Hom.:
4890
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.301
Gnomad AMI
AF:
0.185
Gnomad AMR
AF:
0.296
Gnomad ASJ
AF:
0.187
Gnomad EAS
AF:
0.431
Gnomad SAS
AF:
0.368
Gnomad FIN
AF:
0.176
Gnomad MID
AF:
0.155
Gnomad NFE
AF:
0.185
Gnomad OTH
AF:
0.216
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.242
AC:
36775
AN:
152126
Hom.:
4913
Cov.:
32
AF XY:
0.243
AC XY:
18075
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.301
Gnomad4 AMR
AF:
0.296
Gnomad4 ASJ
AF:
0.187
Gnomad4 EAS
AF:
0.432
Gnomad4 SAS
AF:
0.365
Gnomad4 FIN
AF:
0.176
Gnomad4 NFE
AF:
0.185
Gnomad4 OTH
AF:
0.218
Alfa
AF:
0.204
Hom.:
4490
Bravo
AF:
0.255
Asia WGS
AF:
0.385
AC:
1334
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxSep 17, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.60
DANN
Benign
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2070657; hg19: chr21-27355017; API