21-25880946-G-C

Variant names:

• chr21-25880946-G-C
• rs146774213
• NM_000484.4:c.*724C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000484.4(APP):​c.*724C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APP NM_000484.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.*724C>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798	c.*724C>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1934 AN: 38626 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.0427

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0802

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 414 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 248

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0500 AC: 1934 AN: 38680 Hom.: 0 Cov.: 0 AF XY: 0.0464 AC XY: 894 AN XY: 19258

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0177

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0588

Gnomad4 OTH AF: 0.0786

Alfa AF: 0.00365 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs146774213; hg19: chr21-27253257;