21-26087358-C-G

Variant names:

• chr21-26087358-C-G
• rs2830048
• NM_000484.4:c.355+2585G>C

Variant summary

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

The NM_000484.4(APP):​c.355+2585G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,072 control chromosomes in the GnomAD database, including 15,059 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 0.43 (15059 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.355+2585G>C		intron_variant	Intron 3 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.355+2585G>C		intron_variant	Intron 3 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65643 AN: 151954 Hom.: 15036 Cov.: 33

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.432 AC: 65720 AN: 152072 Hom.: 15059 Cov.: 33 AF XY: 0.435 AC XY: 32360 AN XY: 74328

African (AFR) AF: 0.564 AC: 23397 AN: 41476

American (AMR) AF: 0.534 AC: 8162 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3468

East Asian (EAS) AF: 0.512 AC: 2651 AN: 5180

South Asian (SAS) AF: 0.450 AC: 2172 AN: 4822

European-Finnish (FIN) AF: 0.387 AC: 4083 AN: 10550

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23096 AN: 67984

Other (OTH) AF: 0.397 AC: 839 AN: 2112

Alfa AF: 0.225 Hom.: 468

Bravo AF: 0.448

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.031
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: rs2830048; hg19: chr21-27459674;