rs2830045

Variant names:

• chr21-26086093-A-G
• rs2830045
• NM_000484.4:c.355+3850T>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+3850T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,154 control chromosomes in the GnomAD database, including 7,322 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 0.28 (7322 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350
• Publications: 6 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 (SAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.355+3850T>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+3850T>C		intron_variant	Intron 3 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42431 AN: 152036 Hom.: 7322 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.279 AC: 42425 AN: 152154 Hom.: 7322 Cov.: 33 AF XY: 0.281 AC XY: 20891 AN XY: 74392

African (AFR) AF: 0.0763 AC: 3169 AN: 41530

American (AMR) AF: 0.245 AC: 3749 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1913 AN: 5174

South Asian (SAS) AF: 0.375 AC: 1804 AN: 4816

European-Finnish (FIN) AF: 0.358 AC: 3781 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25154 AN: 67978

Other (OTH) AF: 0.309 AC: 653 AN: 2116

Alfa AF: 0.305 Hom.: 1679

Bravo AF: 0.261

Asia WGS AF: 0.370 AC: 1285 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		0.35
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: rs2830045; hg19: chr21-27458409;