chr21-26030497-T-C

Variant names:

• chr21-26030497-T-C
• rs2830019
• NM_000484.4:c.663-8455A>G

Variant summary

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

The NM_000484.4(APP):​c.663-8455A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,222 control chromosomes in the GnomAD database, including 1,270 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 0.10 (1270 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• Publications: 3 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):

• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alzheimer disease type 1

  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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.663-8455A>G		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.663-8455A>G		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.663-8455A>G		intron	N/A	NP_958816.1	P05067-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.663-8455A>G		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.663-8455A>G		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.495-8455A>G		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15693 AN: 152102 Hom.: 1259 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0836

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

GnomAD4 genome AF: 0.103 AC: 15730 AN: 152222 Hom.: 1270 Cov.: 32 AF XY: 0.109 AC XY: 8113 AN XY: 74424

African (AFR) AF: 0.173 AC: 7168 AN: 41526

American (AMR) AF: 0.177 AC: 2699 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.288 AC: 1489 AN: 5172

South Asian (SAS) AF: 0.137 AC: 661 AN: 4824

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10602

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0343 AC: 2333 AN: 68022

Other (OTH) AF: 0.0860 AC: 182 AN: 2116

Alfa AF: 0.0822 Hom.: 97

Bravo AF: 0.117

Asia WGS AF: 0.218 AC: 757 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.7
DANN	Benign	0.77
PhyloP100		-0.75
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: rs2830019; hg19: chr21-27402812;