rs2830104

Variant names:

• chr21-26165266-A-G
• rs2830104
• NM_000484.4:c.57+5298T>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.57+5298T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,288 control chromosomes in the GnomAD database, including 1,165 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 0.11 (1165 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.356
• 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

ENSG00000224541 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.57+5298T>C		intron_variant	Intron 1 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.57+5298T>C		intron_variant	Intron 1 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16112 AN: 152170 Hom.: 1160 Cov.: 33

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0986

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.106 AC: 16118 AN: 152288 Hom.: 1165 Cov.: 33 AF XY: 0.111 AC XY: 8265 AN XY: 74460

African (AFR) AF: 0.0269 AC: 1119 AN: 41568

American (AMR) AF: 0.165 AC: 2519 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3472

East Asian (EAS) AF: 0.0981 AC: 509 AN: 5190

South Asian (SAS) AF: 0.169 AC: 813 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1754 AN: 10600

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8550 AN: 68026

Other (OTH) AF: 0.107 AC: 226 AN: 2112

Alfa AF: 0.125 Hom.: 683

Bravo AF: 0.101

Asia WGS AF: 0.100 AC: 354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.70
PhyloP100		0.36
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: rs2830104; hg19: chr21-27537584;