21-25955709-T-G

Variant names:

• chr21-25955709-T-G
• rs1555902848
• NM_000484.4:c.1505A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000484.4(APP):​c.1505A>C​(p.Gln502Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1505A>C	p.Gln502Pro	missense	Exon 12 of 18	NP_000475.1
	APP	NM_001204301.2		c.1505A>C	p.Gln502Pro	missense	Exon 12 of 17	NP_001191230.1
	APP	NM_201413.3		c.1448A>C	p.Gln483Pro	missense	Exon 11 of 17	NP_958816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.1505A>C	p.Gln502Pro	missense	Exon 12 of 18	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.1448A>C	p.Gln483Pro	missense	Exon 11 of 17	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.1337A>C	p.Gln446Pro	missense	Exon 11 of 17	ENSP00000398879.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 06, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.27		Gain of glycosylation at Q502 (P = 0.043)
MVP		0.74
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.74
Mutation Taster		=14/86	disease causing

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: rs1555902848; hg19: chr21-27328023;