NM_000484.4:c.1225-31T>C

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.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

Publications

11 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):

cerebral amyloid angiopathy, APP-related
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Alzheimer disease type 1
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=-0.74).

BP6

Variant 21-25976059-A-G is Benign according to our data. Variant chr21-25976059-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APP	NM_000484.4	MANE Select	c.1225-31T>C	intron	N/A	NP_000475.1	P05067-1
APP	NM_001204301.2		c.1225-31T>C	intron	N/A	NP_001191230.1	P05067-9
APP	NM_201413.3		c.1168-31T>C	intron	N/A	NP_958816.1	P05067-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APP	ENST00000346798.8	TSL:1 MANE Select	c.1225-31T>C	intron	N/A	ENSP00000284981.4	P05067-1
APP	ENST00000357903.7	TSL:1	c.1168-31T>C	intron	N/A	ENSP00000350578.3	P05067-8
APP	ENST00000439274.6	TSL:1	c.1057-31T>C	intron	N/A	ENSP00000398879.2	E9PG40

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

GnomAD2 exomes

AF:

0.263

AC:

65701

AN:

250218

AF XY:

0.259

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 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

African (AFR)

AF:

0.266

AC:

8590

AN:

32302

American (AMR)

AF:

0.407

AC:

18174

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4607

AN:

25780

East Asian (EAS)

AF:

0.413

AC:

16240

AN:

39354

South Asian (SAS)

AF:

0.361

AC:

30788

AN:

85170

European-Finnish (FIN)

AF:

0.168

AC:

8838

AN:

52660

Middle Eastern (MID)

AF:

0.197

AC:

1100

AN:

5596

European-Non Finnish (NFE)

AF:

0.194

AC:

205076

AN:

1059172

Other (OTH)

AF:

0.226

AC:

13186

AN:

58400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

11727

23453

35180

46906

58633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7550

15100

22650

30200

37750

<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:

0.231

AC:

35189

AN:

152100

Hom.:

4447

Cov.:

AF XY:

0.233

AC XY:

17352

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.265

AC:

11001

AN:

41486

American (AMR)

AF:

0.293

AC:

4472

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

617

AN:

3472

East Asian (EAS)

AF:

0.432

AC:

2234

AN:

5170

South Asian (SAS)

AF:

0.367

AC:

1769

AN:

4818

European-Finnish (FIN)

AF:

0.176

AC:

1861

AN:

10582

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12581

AN:

67982

Other (OTH)

AF:

0.209

AC:

442

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1381

2762

4142

5523

6904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.208

Hom.:

1558

Bravo

AF:

0.243

Asia WGS

AF:

0.381

AC:

1322

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.9

(source)

DANN

Benign

0.83

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over