rs3991

Variant names:

• chr21-26055940-C-A
• rs3991
• NM_000484.4:c.356-2592G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-26055940-C-A
• chr21-26055940-C-T

Variant summary

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

The NM_000484.4(APP):​c.356-2592G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,140 control chromosomes in the GnomAD database, including 2,656 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 0.17 (2656 hom., cov: 32)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.411
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.237 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.356-2592G>T		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.356-2592G>T		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.356-2592G>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.356-2592G>T		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.356-2592G>T		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.188-2592G>T		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25199 AN: 152022 Hom.: 2655 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.166 AC: 25199 AN: 152140 Hom.: 2656 Cov.: 32 AF XY: 0.162 AC XY: 12048 AN XY: 74390

African (AFR) AF: 0.0537 AC: 2230 AN: 41524

American (AMR) AF: 0.154 AC: 2350 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3472

East Asian (EAS) AF: 0.0407 AC: 211 AN: 5178

South Asian (SAS) AF: 0.0708 AC: 342 AN: 4830

European-Finnish (FIN) AF: 0.215 AC: 2268 AN: 10552

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16294 AN: 67990

Other (OTH) AF: 0.192 AC: 406 AN: 2112

Alfa AF: 0.202 Hom.: 7096

Bravo AF: 0.160

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.69
PhyloP100		-0.41
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3991;

hg19: chr21-27428256;