chr21-25954545-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

14 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 -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 VariationId 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

GnomAD2 exomes

AF:

0.608

AC:

141892

AN:

233330

AF XY:

0.619

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 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

African (AFR)

AF:

0.180

AC:

5652

AN:

31430

American (AMR)

AF:

0.555

AC:

23803

AN:

42916

Ashkenazi Jewish (ASJ)

AF:

0.659

AC:

16701

AN:

25344

East Asian (EAS)

AF:

0.575

AC:

22469

AN:

39058

South Asian (SAS)

AF:

0.619

AC:

51110

AN:

82550

European-Finnish (FIN)

AF:

0.681

AC:

35894

AN:

52730

Middle Eastern (MID)

AF:

0.605

AC:

3401

AN:

5620

European-Non Finnish (NFE)

AF:

0.674

AC:

696633

AN:

1033896

Other (OTH)

AF:

0.622

AC:

35755

AN:

57448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

15736

31472

47209

62945

78681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17326

34652

51978

69304

86630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.520

AC:

79058

AN:

151936

Hom.:

23875

Cov.:

AF XY:

0.521

AC XY:

38686

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.196

AC:

8116

AN:

41418

American (AMR)

AF:

0.531

AC:

8099

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.662

AC:

2298

AN:

3472

East Asian (EAS)

AF:

0.555

AC:

2864

AN:

5162

South Asian (SAS)

AF:

0.601

AC:

2887

AN:

4806

European-Finnish (FIN)

AF:

0.665

AC:

7005

AN:

10530

Middle Eastern (MID)

AF:

0.602

AC:

177

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45862

AN:

67968

Other (OTH)

AF:

0.561

AC:

1184

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1636

3272

4907

6543

8179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.562

Hom.:

23368

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

(source)

DANN

Benign

0.80

PhyloP100

-0.61

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over