21-26170776-C-T

Variant names:

• chr21-26170776-C-T
• rs45476095
• ENST00000357903.7:c.-156G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000357903.7(APP):​c.-156G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 632,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: APP ENST00000357903.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.21
• Publications: 0 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]

ENSG00000224541 (HGNC:):

APP-DT (HGNC:55075): (APP divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.-156G>A		upstream_gene_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.-156G>A		upstream_gene_variant		1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000158 AC: 1 AN: 632266 Hom.: 0 Cov.: 9 AF XY: 0.00000311 AC XY: 1 AN XY: 321176

African (AFR) AF: 0.00 AC: 0 AN: 12284

American (AMR) AF: 0.00 AC: 0 AN: 8656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13034

East Asian (EAS) AF: 0.00 AC: 0 AN: 24476

South Asian (SAS) AF: 0.0000250 AC: 1 AN: 39966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 472004

Other (OTH) AF: 0.00 AC: 0 AN: 30660

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.050
DANN	Benign	0.90
PhyloP100		-2.2
PromoterAI		-0.013	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45476095; hg19: chr21-27543094;