rs148888161

chr21-25891809-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000484.4(APP):c.2124C>T(p.Gly708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,822 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: APP NM_000484.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.832

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 21-25891809-G-A is Benign according to our data. Variant chr21-25891809-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 339629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-25891809-G-A is described in Lovd as [Benign]. Variant chr21-25891809-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.832 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (512/152052) while in subpopulation AFR AF= 0.00752 (312/41472). AF 95% confidence interval is 0.00684. There are 2 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2124C>T	p.Gly708=	synonymous_variant	17/18	ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.2124C>T	p.Gly708=	synonymous_variant	17/18	1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 151934 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00189 AC: 476 AN: 251332 Hom.: 1 AF XY: 0.00175 AC XY: 238 AN XY: 135836

Gnomad AFR exome AF: 0.00744

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00169

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00209 AC: 3050 AN: 1461770 Hom.: 3 Cov.: 32 AF XY: 0.00197 AC XY: 1435 AN XY: 727190

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00337 AC: 512 AN: 152052 Hom.: 2 Cov.: 32 AF XY: 0.00304 AC XY: 226 AN XY: 74316

Gnomad4 AFR AF: 0.00752

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00133

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00352

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	APP: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Alzheimer disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

APP POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 1992

- -

Alzheimer disease type 1;C2751536:Cerebral amyloid angiopathy, APP-related Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.9
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148888161; hg19: chr21-27264121; COSMIC: COSV60993692;