Genetic Variant APP:c.-156G>C (chr21-26170776-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000357903.7(APP):c.-156G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 784,406 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 84 hom. )

Consequence

APP
ENST00000357903.7 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.21

Publications

4 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 links:

ENSG00000224541 (HGNC:):

ENSG00000224541 links:

APP-DT (HGNC:55075): (APP divergent transcript)

APP-DT 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=-0.93).

BP6

Variant 21-26170776-C-G is Benign according to our data. Variant chr21-26170776-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 339655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.-156G>C		upstream_gene_variant		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.-156G>C		upstream_gene_variant		1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.00826

AC:

1256

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0701

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.00479

GnomAD4 exome

AF:

0.00678

AC:

4286

AN:

632238

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

2140

AN XY:

321166

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

12284

American (AMR)

AF:

0.0326

AC:

282

AN:

8654

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

13034

East Asian (EAS)

AF:

0.0717

AC:

1755

AN:

24470

South Asian (SAS)

AF:

0.00510

AC:

204

AN:

39962

European-Finnish (FIN)

AF:

0.0174

AC:

504

AN:

28900

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

2286

European-Non Finnish (NFE)

AF:

0.00273

AC:

1289

AN:

471990

Other (OTH)

AF:

0.00682

AC:

209

AN:

30658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

213

426

638

851

1064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00820

AC:

1248

AN:

152168

Hom.:

Cov.:

AF XY:

0.00957

AC XY:

712

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41528

American (AMR)

AF:

0.0260

AC:

398

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.0697

AC:

360

AN:

5166

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

67968

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00482

Hom.:

Bravo

AF:

0.00996

Asia WGS

AF:

0.0330

AC:

113

AN:

3460

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 24, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Early-onset autosomal dominant Alzheimer disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.93

CADD

Benign

0.044

(source)

DANN

Benign

0.67

PhyloP100

-2.2

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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