dbSNP rs2829997: APP:c.1687+45C>T (chr21-25954545-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000484.4(APP):c.1687+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,522,928 control chromosomes in the GnomAD database, including 318,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 23875 hom., cov: 31)

Exomes 𝑓: 0.65 ( 294433 hom. )

Consequence

APP
NM_000484.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.615

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:

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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=-0.79).

BP6

Variant 21-25954545-G-A is Benign according to our data. Variant chr21-25954545-G-A is described in ClinVar as [Benign]. Clinvar id is 1249693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.1687+45C>T		intron_variant	Intron 13 of 17	ENST00000346798.8	NP_000475.1	P05067-1A0A140VJC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 link	c.1687+45C>T		intron_variant	Intron 13 of 17	1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.521

AC:

79047

AN:

151818

Hom.:

23866

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.622

Gnomad AMR

AF:

0.530

Gnomad ASJ

AF:

0.662

Gnomad EAS

AF:

0.555

Gnomad SAS

AF:

0.599

Gnomad FIN

AF:

0.665

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.564

GnomAD3 exomes

AF:

0.608

AC:

141892

AN:

233330

Hom.:

44707

AF XY:

0.619

AC XY:

77682

AN XY:

125420

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.658

Gnomad EAS exome

AF:

0.555

Gnomad SAS exome

AF:

0.621

Gnomad FIN exome

AF:

0.682

Gnomad NFE exome

AF:

0.671

Gnomad OTH exome

AF:

0.622

GnomAD4 exome

AF:

0.650

AC:

891418

AN:

1370992

Hom.:

294433

Cov.:

AF XY:

0.651

AC XY:

446202

AN XY:

684898

show subpopulations

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.555

Gnomad4 ASJ exome

AF:

0.659

Gnomad4 EAS exome

AF:

0.575

Gnomad4 SAS exome

AF:

0.619

Gnomad4 FIN exome

AF:

0.681

Gnomad4 NFE exome

AF:

0.674

Gnomad4 OTH exome

AF:

0.622

GnomAD4 genome

AF:

0.520

AC:

79058

AN:

151936

Hom.:

23875

Cov.:

AF XY:

0.521

AC XY:

38686

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.531

Gnomad4 ASJ

AF:

0.662

Gnomad4 EAS

AF:

0.555

Gnomad4 SAS

AF:

0.601

Gnomad4 FIN

AF:

0.665

Gnomad4 NFE

AF:

0.675

Gnomad4 OTH

AF:

0.561

Alfa

AF:

0.624

Hom.:

17491

Bravo

AF:

0.496

Asia WGS

AF:

0.555

AC:

1932

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.3

DANN

Benign

0.80

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