rs440666

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000484.4(APP):​c.1459-106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,522,872 control chromosomes in the GnomAD database, including 407,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38203 hom., cov: 32)
Exomes 𝑓: 0.73 ( 369463 hom. )

Consequence

APP
NM_000484.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.337
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 21-25955861-T-C is Benign according to our data. Variant chr21-25955861-T-C is described in ClinVar as [Benign]. Clinvar id is 1250029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APPNM_000484.4 linkuse as main transcriptc.1459-106A>G intron_variant ENST00000346798.8 NP_000475.1 P05067-1A0A140VJC8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APPENST00000346798.8 linkuse as main transcriptc.1459-106A>G intron_variant 1 NM_000484.4 ENSP00000284981.4 P05067-1

Frequencies

GnomAD3 genomes
AF:
0.706
AC:
107353
AN:
151968
Hom.:
38177
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.660
Gnomad AMI
AF:
0.620
Gnomad AMR
AF:
0.693
Gnomad ASJ
AF:
0.706
Gnomad EAS
AF:
0.612
Gnomad SAS
AF:
0.747
Gnomad FIN
AF:
0.724
Gnomad MID
AF:
0.661
Gnomad NFE
AF:
0.741
Gnomad OTH
AF:
0.712
GnomAD4 exome
AF:
0.733
AC:
1005099
AN:
1370786
Hom.:
369463
AF XY:
0.735
AC XY:
505017
AN XY:
686948
show subpopulations
Gnomad4 AFR exome
AF:
0.651
Gnomad4 AMR exome
AF:
0.685
Gnomad4 ASJ exome
AF:
0.707
Gnomad4 EAS exome
AF:
0.662
Gnomad4 SAS exome
AF:
0.763
Gnomad4 FIN exome
AF:
0.741
Gnomad4 NFE exome
AF:
0.739
Gnomad4 OTH exome
AF:
0.720
GnomAD4 genome
AF:
0.706
AC:
107423
AN:
152086
Hom.:
38203
Cov.:
32
AF XY:
0.705
AC XY:
52418
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.659
Gnomad4 AMR
AF:
0.693
Gnomad4 ASJ
AF:
0.706
Gnomad4 EAS
AF:
0.612
Gnomad4 SAS
AF:
0.748
Gnomad4 FIN
AF:
0.724
Gnomad4 NFE
AF:
0.741
Gnomad4 OTH
AF:
0.709
Alfa
AF:
0.730
Hom.:
80452
Bravo
AF:
0.698
Asia WGS
AF:
0.677
AC:
2356
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.90
DANN
Benign
0.30

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: rs440666; hg19: chr21-27328175; COSMIC: COSV60993298; API