rs400603

Variant names:

• chr21-25952974-G-A
• rs400603
• NM_000484.4:c.1687+1616C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-25952974-G-A
• chr21-25952974-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.1687+1616C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 152,252 control chromosomes in the GnomAD database, including 64,229 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 0.92 (64229 hom., cov: 33)
• Consequence: APP NM_000484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 7 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.926 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+1616C>T		intron	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.1687+1616C>T		intron	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.1630+1616C>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+1616C>T		intron	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.1630+1616C>T		intron	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.1519+1616C>T		intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139684 AN: 152134 Hom.: 64184 Cov.: 33

Gnomad AFR AF: 0.912

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.911

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

GnomAD4 genome AF: 0.918 AC: 139785 AN: 152252 Hom.: 64229 Cov.: 33 AF XY: 0.918 AC XY: 68307 AN XY: 74444

African (AFR) AF: 0.912 AC: 37888 AN: 41526

American (AMR) AF: 0.912 AC: 13951 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3175 AN: 3472

East Asian (EAS) AF: 0.811 AC: 4204 AN: 5184

South Asian (SAS) AF: 0.895 AC: 4316 AN: 4822

European-Finnish (FIN) AF: 0.928 AC: 9845 AN: 10612

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63436 AN: 68030

Other (OTH) AF: 0.911 AC: 1920 AN: 2108

Alfa AF: 0.927 Hom.: 40581

Bravo AF: 0.915

Asia WGS AF: 0.885 AC: 3079 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.4
DANN	Benign	0.27
PhyloP100		0.062
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: rs400603;

hg19: chr21-27325288;