dbSNP rs3827166: APP:c.225+2978A>C (chr21-26109001-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000484.4(APP):c.225+2978A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 152,306 control chromosomes in the GnomAD database, including 888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.095 ( 888 hom., cov: 32)

Consequence

APP
NM_000484.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Alzheimer disease type 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
cerebral amyloid angiopathy, APP-related
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ABeta amyloidosis, Arctic type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, dutch type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Iowa type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Italian type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaA21G amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaL34V amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

APP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.225+2978A>C		intron_variant	Intron 2 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.225+2978A>C		intron_variant	Intron 2 of 17	1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.0954

AC:

14518

AN:

152188

Hom.:

885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.147

Gnomad ASJ

AF:

0.0997

Gnomad EAS

AF:

0.0925

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.0963

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0954

AC:

14524

AN:

152306

Hom.:

888

Cov.:

AF XY:

0.0997

AC XY:

7423

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0360

AC:

1495

AN:

41570

American (AMR)

AF:

0.147

AC:

2245

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0997

AC:

346

AN:

3472

East Asian (EAS)

AF:

0.0922

AC:

478

AN:

5186

South Asian (SAS)

AF:

0.133

AC:

643

AN:

4828

European-Finnish (FIN)

AF:

0.149

AC:

1587

AN:

10618

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7336

AN:

68014

Other (OTH)

AF:

0.0953

AC:

201

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

650

1300

1949

2599

3249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

451

Bravo

AF:

0.0923

Asia WGS

AF:

0.0900

AC:

318

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.4

(source)

DANN

Benign

0.53

PhyloP100

0.085

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over