21-26170731-C-G

Variant names:

• chr21-26170731-C-G
• rs459543
• ENST00000474136.5:n.16G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000474136.5(APP):​n.16G>C variant causes a non coding transcript exon 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 ENST00000474136.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.809
• Publications: 7 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
APP	NM_000484.4	c.-111G>C		5_prime_UTR_variant	Exon 1 of 18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.-111G>C		5_prime_UTR_variant	Exon 1 of 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

African (AFR) AF: 0.184 AC: 3617 AN: 19618

American (AMR) AF: 0.0947 AC: 1210 AN: 12780

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 67 AN: 16086

East Asian (EAS) AF: 0.186 AC: 5013 AN: 26960

South Asian (SAS) AF: 0.0626 AC: 3283 AN: 52446

European-Finnish (FIN) AF: 0.0614 AC: 1856 AN: 30250

Middle Eastern (MID) AF: 0.0255 AC: 79 AN: 3094

European-Non Finnish (NFE) AF: 0.0237 AC: 18667 AN: 787196

Other (OTH) AF: 0.0480 AC: 2057 AN: 42826

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

African (AFR) AF: 0.187 AC: 7772 AN: 41502

American (AMR) AF: 0.0684 AC: 1046 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1030 AN: 5126

South Asian (SAS) AF: 0.0723 AC: 349 AN: 4828

European-Finnish (FIN) AF: 0.0656 AC: 696 AN: 10604

Middle Eastern (MID) AF: 0.0174 AC: 5 AN: 288

European-Non Finnish (NFE) AF: 0.0239 AC: 1626 AN: 67942

Other (OTH) AF: 0.0735 AC: 155 AN: 2108

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

Sep 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Alzheimer disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.81
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs459543; hg19: chr21-27543049;