21-26170731-C-G

Position:

• chr21-26170731-C-G

Variant summary

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

The NM_000484.4(APP):​c.-111G>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 0.0425 in 1,143,326 control chromosomes in the GnomAD database, including 2,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (966 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1471 hom.)
• Consequence: APP NM_000484.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.809

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-26170731-C-G is Benign according to our data. Variant chr21-26170731-C-G is described in ClinVar as [Benign]. Clinvar id is 339653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.-111G>C		5_prime_UTR_variant	1/18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.-111G>C		5_prime_UTR_variant	1/18	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12673 AN: 151960 Hom.: 962 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.0727

Gnomad FIN AF: 0.0656

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0743

GnomAD4 exome AF: 0.0362 AC: 35849 AN: 991256 Hom.: 1471 Cov.: 13 AF XY: 0.0362 AC XY: 17877 AN XY: 493254

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.0947

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.0626

Gnomad4 FIN exome AF: 0.0614

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0480

GnomAD4 genome AF: 0.0835 AC: 12691 AN: 152070 Hom.: 966 Cov.: 33 AF XY: 0.0847 AC XY: 6297 AN XY: 74354

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0684

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.0723

Gnomad4 FIN AF: 0.0656

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.0181 Hom.: 6

Bravo AF: 0.0895

Asia WGS AF: 0.139 AC: 479 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2018	- -

Alzheimer disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs459543; hg19: chr21-27543049;