rs3787637

Variant names:

• chr21-25999352-C-T
• rs3787637
• NM_000484.4:c.1033+663G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000484.4(APP):​c.1033+663G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 152,174 control chromosomes in the GnomAD database, including 138 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 0.030 (138 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1033+663G>A		intron_variant	Intron 7 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1033+663G>A		intron_variant	Intron 7 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4566 AN: 152056 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.0858

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0244

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

GnomAD4 genome AF: 0.0300 AC: 4566 AN: 152174 Hom.: 138 Cov.: 32 AF XY: 0.0335 AC XY: 2494 AN XY: 74396

African (AFR) AF: 0.00621 AC: 258 AN: 41538

American (AMR) AF: 0.0667 AC: 1019 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3464

East Asian (EAS) AF: 0.0562 AC: 291 AN: 5180

South Asian (SAS) AF: 0.0857 AC: 412 AN: 4810

European-Finnish (FIN) AF: 0.0667 AC: 706 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1816 AN: 68004

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0298 Hom.: 34

Bravo AF: 0.0282

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.055
DANN	Benign	0.80
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3787637; hg19: chr21-27371667;