chr21-25912793-T-G

Variant names:

• chr21-25912793-T-G
• rs2829983
• NM_000484.4:c.1688-831A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000484.4(APP):​c.1688-831A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,166 control chromosomes in the GnomAD database, including 4,107 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (4107 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• Publications: 4 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]

APP Gene-Disease associations (from GenCC):

• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ABeta amyloidosis, Arctic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, dutch type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Iowa type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Italian type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaA21G amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaL34V amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.1688-831A>C		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.1688-831A>C		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.1631-831A>C		intron	N/A	NP_958816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.1688-831A>C		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.1631-831A>C		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.1520-831A>C		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29717 AN: 152048 Hom.: 4101 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.196 AC: 29759 AN: 152166 Hom.: 4107 Cov.: 32 AF XY: 0.196 AC XY: 14541 AN XY: 74376

African (AFR) AF: 0.393 AC: 16290 AN: 41468

American (AMR) AF: 0.203 AC: 3097 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3466

East Asian (EAS) AF: 0.127 AC: 657 AN: 5178

South Asian (SAS) AF: 0.179 AC: 862 AN: 4820

European-Finnish (FIN) AF: 0.100 AC: 1065 AN: 10606

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7166 AN: 68020

Other (OTH) AF: 0.163 AC: 345 AN: 2114

Alfa AF: 0.125 Hom.: 2097

Bravo AF: 0.211

Asia WGS AF: 0.163 AC: 563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2829983; hg19: chr21-27285105;