chr21-25891785-G-C

Variant names:

• chr21-25891785-G-C
• rs145564988
• NM_000484.4:c.2148C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000484.4(APP):​c.2148C>G​(p.Ile716Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I716F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.332
• 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):

• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000484.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-25891787-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2498894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 21-25891785-G-C is Pathogenic according to our data. Variant chr21-25891785-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1298879.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2148C>G	p.Ile716Met	missense	Exon 17 of 18	NP_000475.1
	APP	NM_001204301.2		c.2094C>G	p.Ile698Met	missense	Exon 16 of 17	NP_001191230.1
	APP	NM_201413.3		c.2091C>G	p.Ile697Met	missense	Exon 16 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.2148C>G	p.Ile716Met	missense	Exon 17 of 18	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.2091C>G	p.Ile697Met	missense	Exon 16 of 17	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.1980C>G	p.Ile660Met	missense	Exon 16 of 17	ENSP00000398879.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.90	L
PhyloP100		-0.33
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.014	D
Sift4G	Benign	0.094	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.63		Gain of helix (P = 0.0496)
MVP		0.85
MPC		1.2
ClinPred		0.92	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.91
Mutation Taster		=2/98	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: rs145564988; hg19: chr21-27264097;