21-25901777-T-G

Variant names:

• chr21-25901777-T-G
• rs1787438
• NM_000484.4:c.1963+3247A>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.1963+3247A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 152,016 control chromosomes in the GnomAD database, including 58,473 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 0.88 (58473 hom., cov: 30)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.281
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.901 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.1963+3247A>C		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.1910-4104A>C		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.1906+3247A>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.1963+3247A>C		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.1906+3247A>C		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.1795+3247A>C		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133061 AN: 151898 Hom.: 58435 Cov.: 30

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.861

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.875

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

GnomAD4 genome AF: 0.876 AC: 133153 AN: 152016 Hom.: 58473 Cov.: 30 AF XY: 0.874 AC XY: 64901 AN XY: 74288

African (AFR) AF: 0.828 AC: 34288 AN: 41418

American (AMR) AF: 0.895 AC: 13673 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3154 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4133 AN: 5152

South Asian (SAS) AF: 0.884 AC: 4250 AN: 4808

European-Finnish (FIN) AF: 0.861 AC: 9086 AN: 10552

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61689 AN: 68012

Other (OTH) AF: 0.875 AC: 1848 AN: 2112

Alfa AF: 0.898 Hom.: 105183

Bravo AF: 0.875

Asia WGS AF: 0.868 AC: 3020 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	1.5
DANN	Benign	0.64
PhyloP100		-0.28
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: rs1787438; hg19: chr21-27274089;