Variant 21-25976059-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000484.4(APP):c.1225-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,555,134 control chromosomes in the GnomAD database, including 41,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4447 hom., cov: 32)

Exomes 𝑓: 0.22 ( 36999 hom. )

Consequence

APP
NM_000484.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.24

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]

APP links:

APP (HGNC:):

APP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 21-25976059-A-G is Benign according to our data. Variant chr21-25976059-A-G is described in ClinVar as [Benign]. Clinvar id is 1233599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
APP	NM_000484.4 linkuse as main transcript	c.1225-31T>C		intron_variant		ENST00000346798.8	NP_000475.1	P05067-1A0A140VJC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 linkuse as main transcript	c.1225-31T>C		intron_variant		1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35147

AN:

151982

Hom.:

4429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.207

GnomAD3 exomes

AF:

0.263

AC:

65701

AN:

250218

Hom.:

10193

AF XY:

0.259

AC XY:

35013

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.421

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.447

Gnomad SAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.219

AC:

306599

AN:

1403034

Hom.:

36999

Cov.:

AF XY:

0.221

AC XY:

155260

AN XY:

701810

show subpopulations

Gnomad4 AFR exome

AF:

0.266

Gnomad4 AMR exome

AF:

0.407

Gnomad4 ASJ exome

AF:

0.179

Gnomad4 EAS exome

AF:

0.413

Gnomad4 SAS exome

AF:

0.361

Gnomad4 FIN exome

AF:

0.168

Gnomad4 NFE exome

AF:

0.194

Gnomad4 OTH exome

AF:

0.226

GnomAD4 genome

AF:

0.231

AC:

35189

AN:

152100

Hom.:

4447

Cov.:

AF XY:

0.233

AC XY:

17352

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.265

Gnomad4 AMR

AF:

0.293

Gnomad4 ASJ

AF:

0.178

Gnomad4 EAS

AF:

0.432

Gnomad4 SAS

AF:

0.367

Gnomad4 FIN

AF:

0.176

Gnomad4 NFE

AF:

0.185

Gnomad4 OTH

AF:

0.209

Alfa

AF:

0.211

Hom.:

1044

Bravo

AF:

0.243

Asia WGS

AF:

0.381

AC:

1322

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 submitter	clinical testing	GeneDx	Aug 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.9

DANN

Benign

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over