rs2096488

Variant names:

• chr21-25971876-A-C
• rs2096488
• NM_000484.4:c.1458+3194T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-25971876-A-C
• chr21-25971876-A-T

Variant summary

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

The NM_000484.4(APP):​c.1458+3194T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,182 control chromosomes in the GnomAD database, including 3,106 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 0.17 (3106 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.833
• 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1458+3194T>G		intron_variant	Intron 11 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1458+3194T>G		intron_variant	Intron 11 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26475 AN: 152064 Hom.: 3103 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.174 AC: 26482 AN: 152182 Hom.: 3106 Cov.: 32 AF XY: 0.181 AC XY: 13483 AN XY: 74386

African (AFR) AF: 0.0377 AC: 1565 AN: 41562

American (AMR) AF: 0.154 AC: 2361 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1851 AN: 5160

South Asian (SAS) AF: 0.264 AC: 1269 AN: 4814

European-Finnish (FIN) AF: 0.310 AC: 3281 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14632 AN: 67994

Other (OTH) AF: 0.191 AC: 404 AN: 2116

Alfa AF: 0.192 Hom.: 4032

Bravo AF: 0.156

Asia WGS AF: 0.300 AC: 1041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.1
DANN	Benign	0.88
PhyloP100		0.83
Mutation Taster		=99/1	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: rs2096488; hg19: chr21-27344189;