rs7278838

Variant names:

• chr21-26002289-C-A
• rs7278838
• NM_000484.4:c.866-2107G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-26002289-C-A
• chr21-26002289-C-G

Variant summary

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

The NM_000484.4(APP):​c.866-2107G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 115,088 control chromosomes in the GnomAD database, including 10,454 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 0.46 (10454 hom., cov: 31)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.866-2107G>T		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.866-2107G>T		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.866-2107G>T		intron	N/A	NP_958816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.866-2107G>T		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.866-2107G>T		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.698-2107G>T		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 52863 AN: 114972 Hom.: 10422 Cov.: 31

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.305

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.436

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

GnomAD4 genome AF: 0.460 AC: 52945 AN: 115088 Hom.: 10454 Cov.: 31 AF XY: 0.462 AC XY: 26146 AN XY: 56532

African (AFR) AF: 0.588 AC: 20934 AN: 35592

American (AMR) AF: 0.540 AC: 6679 AN: 12376

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 773 AN: 2410

East Asian (EAS) AF: 0.529 AC: 2188 AN: 4140

South Asian (SAS) AF: 0.510 AC: 2007 AN: 3936

European-Finnish (FIN) AF: 0.390 AC: 2906 AN: 7458

Middle Eastern (MID) AF: 0.306 AC: 66 AN: 216

European-Non Finnish (NFE) AF: 0.353 AC: 16549 AN: 46840

Other (OTH) AF: 0.436 AC: 680 AN: 1558

Alfa AF: 0.282 Hom.: 21407

Bravo AF: 0.367

Asia WGS AF: 0.412 AC: 1433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.50
DANN	Benign	0.84
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7278838; hg19: chr21-27374604;