rs114675472

chr21-25975945-A-Gchr21-25975945-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000484.4(APP):c.1299+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,612,114 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (46 hom.)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-25975945-A-G is Benign according to our data. Variant chr21-25975945-A-G is described in ClinVar as [Benign]. Clinvar id is 339639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1764/152344) while in subpopulation AFR AF= 0.0399 (1660/41578). AF 95% confidence interval is 0.0383. There are 29 homozygotes in gnomad4. There are 802 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1760 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.1299+9T>C		intron_variant		ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.1299+9T>C		intron_variant		1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1760 AN: 152226 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00317 AC: 797 AN: 251292 Hom.: 15 AF XY: 0.00228 AC XY: 310 AN XY: 135826

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00126 AC: 1845 AN: 1459770 Hom.: 46 Cov.: 30 AF XY: 0.00109 AC XY: 795 AN XY: 726352

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000820

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.0116 AC: 1764 AN: 152344 Hom.: 29 Cov.: 32 AF XY: 0.0108 AC XY: 802 AN XY: 74510

Gnomad4 AFR AF: 0.0399

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00521 Hom.: 9

Bravo AF: 0.0136

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2018	- -

Alzheimer disease Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.071
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs114675472; hg19: chr21-27348258;