rs2829997

Variant names:

• chr21-25954545-G-A
• rs2829997
• NM_000484.4:c.1687+45C>T

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.1687+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,522,928 control chromosomes in the GnomAD database, including 318,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23875 hom., cov: 31)
  • Exomes 𝑓: 0.65 (294433 hom.)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.615
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.79).
• BP6: Variant 21-25954545-G-A is Benign according to our data. Variant chr21-25954545-G-A is described in ClinVar as Benign. ClinVar VariationId is 1249693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.1687+45C>T		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.1687+45C>T		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.1630+45C>T		intron	N/A	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.1687+45C>T		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.1630+45C>T		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.1519+45C>T		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79047 AN: 151818 Hom.: 23866 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.564

GnomAD2 exomes AF: 0.608 AC: 141892 AN: 233330 AF XY: 0.619

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.658

Gnomad EAS exome AF: 0.555

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.671

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.650 AC: 891418 AN: 1370992 Hom.: 294433 Cov.: 22 AF XY: 0.651 AC XY: 446202 AN XY: 684898

African (AFR) AF: 0.180 AC: 5652 AN: 31430

American (AMR) AF: 0.555 AC: 23803 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 16701 AN: 25344

East Asian (EAS) AF: 0.575 AC: 22469 AN: 39058

South Asian (SAS) AF: 0.619 AC: 51110 AN: 82550

European-Finnish (FIN) AF: 0.681 AC: 35894 AN: 52730

Middle Eastern (MID) AF: 0.605 AC: 3401 AN: 5620

European-Non Finnish (NFE) AF: 0.674 AC: 696633 AN: 1033896

Other (OTH) AF: 0.622 AC: 35755 AN: 57448

GnomAD4 genome AF: 0.520 AC: 79058 AN: 151936 Hom.: 23875 Cov.: 31 AF XY: 0.521 AC XY: 38686 AN XY: 74234

African (AFR) AF: 0.196 AC: 8116 AN: 41418

American (AMR) AF: 0.531 AC: 8099 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2298 AN: 3472

East Asian (EAS) AF: 0.555 AC: 2864 AN: 5162

South Asian (SAS) AF: 0.601 AC: 2887 AN: 4806

European-Finnish (FIN) AF: 0.665 AC: 7005 AN: 10530

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45862 AN: 67968

Other (OTH) AF: 0.561 AC: 1184 AN: 2110

Alfa AF: 0.562 Hom.: 23368

Bravo AF: 0.496

Asia WGS AF: 0.555 AC: 1932 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.80
PhyloP100		-0.61
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: rs2829997; hg19: chr21-27326859;