21-26063209-C-T

Variant names:

• chr21-26063209-C-T
• rs2830036
• NM_000484.4:c.356-9861G>A

Variant summary

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

The NM_000484.4(APP):​c.356-9861G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 151,994 control chromosomes in the GnomAD database, including 2,775 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 0.17 (2775 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.289
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.257 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.356-9861G>A		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.356-9861G>A		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.356-9861G>A		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.356-9861G>A		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.356-9861G>A		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.188-9861G>A		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25831 AN: 151876 Hom.: 2762 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.170 AC: 25844 AN: 151994 Hom.: 2775 Cov.: 32 AF XY: 0.173 AC XY: 12843 AN XY: 74282

African (AFR) AF: 0.0431 AC: 1788 AN: 41466

American (AMR) AF: 0.264 AC: 4028 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 529 AN: 3464

East Asian (EAS) AF: 0.186 AC: 964 AN: 5180

South Asian (SAS) AF: 0.217 AC: 1044 AN: 4806

European-Finnish (FIN) AF: 0.245 AC: 2582 AN: 10540

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.211 AC: 14360 AN: 67950

Other (OTH) AF: 0.167 AC: 352 AN: 2104

Alfa AF: 0.186 Hom.: 1864

Bravo AF: 0.164

Asia WGS AF: 0.191 AC: 664 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-0.29
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: rs2830036; hg19: chr21-27435525;