rs440666

Variant names:

• chr21-25955861-T-C
• rs440666
• NM_000484.4:c.1459-106A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000484.4(APP):​c.1459-106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,522,872 control chromosomes in the GnomAD database, including 407,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38203 hom., cov: 32)
  • Exomes 𝑓: 0.73 (369463 hom.)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.337
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-25955861-T-C is Benign according to our data. Variant chr21-25955861-T-C is described in ClinVar as Benign. ClinVar VariationId is 1250029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.1459-106A>G		intron_variant	Intron 11 of 17	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.1459-106A>G		intron_variant	Intron 11 of 17	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107353 AN: 151968 Hom.: 38177 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.733 AC: 1005099 AN: 1370786 Hom.: 369463 AF XY: 0.735 AC XY: 505017 AN XY: 686948

African (AFR) AF: 0.651 AC: 20545 AN: 31544

American (AMR) AF: 0.685 AC: 30321 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 17982 AN: 25450

East Asian (EAS) AF: 0.662 AC: 25733 AN: 38888

South Asian (SAS) AF: 0.763 AC: 63935 AN: 83790

European-Finnish (FIN) AF: 0.741 AC: 35685 AN: 48128

Middle Eastern (MID) AF: 0.696 AC: 3895 AN: 5600

European-Non Finnish (NFE) AF: 0.739 AC: 765749 AN: 1035836

Other (OTH) AF: 0.720 AC: 41254 AN: 57258

GnomAD4 genome AF: 0.706 AC: 107423 AN: 152086 Hom.: 38203 Cov.: 32 AF XY: 0.705 AC XY: 52418 AN XY: 74334

African (AFR) AF: 0.659 AC: 27360 AN: 41488

American (AMR) AF: 0.693 AC: 10575 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3472

East Asian (EAS) AF: 0.612 AC: 3164 AN: 5172

South Asian (SAS) AF: 0.748 AC: 3602 AN: 4818

European-Finnish (FIN) AF: 0.724 AC: 7645 AN: 10564

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50368 AN: 67990

Other (OTH) AF: 0.709 AC: 1500 AN: 2116

Alfa AF: 0.724 Hom.: 114838

Bravo AF: 0.698

Asia WGS AF: 0.677 AC: 2356 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.90
DANN	Benign	0.30
PhyloP100		-0.34
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: rs440666; hg19: chr21-27328175; COSMIC: COSV60993298;