rs45476095

Positions:

• chr21-26170776-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000357903.7(APP):​c.-156G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 784,406 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (84 hom.)
• Consequence: APP ENST00000357903.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.21

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-26170776-C-G is Benign according to our data. Variant chr21-26170776-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 339655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.-156G>C		upstream_gene_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.-156G>C		upstream_gene_variant		1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 1256 AN: 152060 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0701

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.00678 AC: 4286 AN: 632238 Hom.: 84 Cov.: 9 AF XY: 0.00666 AC XY: 2140 AN XY: 321166

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0717

Gnomad4 SAS exome AF: 0.00510

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.00820 AC: 1248 AN: 152168 Hom.: 31 Cov.: 33 AF XY: 0.00957 AC XY: 712 AN XY: 74398

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0697

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00482 Hom.: 1

Bravo AF: 0.00996

Asia WGS AF: 0.0330 AC: 113 AN: 3460

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	See Variant Classification Assertion Criteria. -

Early-onset autosomal dominant Alzheimer disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.044
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs45476095; hg19: chr21-27543094;