rs1041420

Variant names:

• chr21-26071334-G-A
• rs1041420
• NM_000484.4:c.356-17986C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-26071334-G-A
• chr21-26071334-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000484.4(APP):​c.356-17986C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,850 control chromosomes in the GnomAD database, including 4,086 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4086 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.136
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.356-17986C>T		intron	N/A	NP_000475.1
	APP	NM_001204301.2		c.356-17986C>T		intron	N/A	NP_001191230.1
	APP	NM_201413.3		c.356-17986C>T		intron	N/A	NP_958816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.356-17986C>T		intron	N/A	ENSP00000284981.4
	APP	ENST00000357903.7	TSL:1	c.356-17986C>T		intron	N/A	ENSP00000350578.3
	APP	ENST00000439274.6	TSL:1	c.188-17986C>T		intron	N/A	ENSP00000398879.2

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34930 AN: 151732 Hom.: 4069 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.214

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34957 AN: 151850 Hom.: 4086 Cov.: 32 AF XY: 0.230 AC XY: 17040 AN XY: 74194

African (AFR) AF: 0.239 AC: 9877 AN: 41396

American (AMR) AF: 0.283 AC: 4314 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 564 AN: 3462

East Asian (EAS) AF: 0.181 AC: 929 AN: 5132

South Asian (SAS) AF: 0.216 AC: 1039 AN: 4818

European-Finnish (FIN) AF: 0.248 AC: 2603 AN: 10500

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15004 AN: 67972

Other (OTH) AF: 0.211 AC: 446 AN: 2110

Alfa AF: 0.221 Hom.: 10816

Bravo AF: 0.233

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.2
DANN	Benign	0.89
PhyloP100		-0.14
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: rs1041420; hg19: chr21-27443650;