21-26128343-T-G

Variant names:

• chr21-26128343-T-G
• rs2830072
• NM_000484.4:c.58-16197A>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.58-16197A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 152,122 control chromosomes in the GnomAD database, including 14,271 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 0.39 (14271 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 6 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

LOC124900466 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 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.58-16197A>C		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.58-16197A>C		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.58-16197A>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.58-16197A>C		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.58-16197A>C		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.58-38271A>C		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59451 AN: 152004 Hom.: 14265 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.422

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

GnomAD4 genome AF: 0.391 AC: 59452 AN: 152122 Hom.: 14271 Cov.: 33 AF XY: 0.390 AC XY: 28965 AN XY: 74364

African (AFR) AF: 0.108 AC: 4472 AN: 41512

American (AMR) AF: 0.357 AC: 5454 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2173 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2297 AN: 5168

South Asian (SAS) AF: 0.465 AC: 2247 AN: 4828

European-Finnish (FIN) AF: 0.506 AC: 5350 AN: 10576

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36017 AN: 67976

Other (OTH) AF: 0.424 AC: 896 AN: 2112

Alfa AF: 0.436 Hom.: 2447

Bravo AF: 0.366

Asia WGS AF: 0.442 AC: 1535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		0.10
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: rs2830072; hg19: chr21-27500660;