rs145081708

Variant names:

• chr21-26051070-A-G
• rs145081708
• NM_000484.4:c.592T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000484.4(APP):​c.592T>C​(p.Ser198Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.45
• Publications: 13 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014454454).
• BP6: Variant 21-26051070-A-G is Benign according to our data. Variant chr21-26051070-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 339645.
• BS2: High AC in GnomAd4 at 61 AD gene.

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.592T>C	p.Ser198Pro	missense	Exon 5 of 18	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.592T>C	p.Ser198Pro	missense	Exon 5 of 17	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.592T>C	p.Ser198Pro	missense	Exon 5 of 17	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.592T>C	p.Ser198Pro	missense	Exon 5 of 18	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.592T>C	p.Ser198Pro	missense	Exon 5 of 17	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.424T>C	p.Ser142Pro	missense	Exon 4 of 17	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000684 AC: 172 AN: 251438 AF XY: 0.000640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000311 AC: 454 AN: 1461882 Hom.: 1 Cov.: 31 AF XY: 0.000311 AC XY: 226 AN XY: 727246

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 301 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000629 AC: 70 AN: 1112006

Other (OTH) AF: 0.000993 AC: 60 AN: 60396

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000636 Hom.: 1

Bravo AF: 0.000382

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Alzheimer disease (2)
-	-	2	not specified (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.014	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.088	T
Polyphen		0.96	D
Vest4		0.54
MVP		0.93
MPC		0.64
ClinPred		0.14	T
GERP RS		5.7
PromoterAI		0.0058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.31
Mutation Taster		=85/15	polymorphism

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: rs145081708; hg19: chr21-27423386;