NM_000484.4:c.-111G>T

Variant names:

• chr21-26170731-C-A
• rs459543
• NM_000484.4:c.-111G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000484.4(APP):​c.-111G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 991,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: APP NM_000484.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.809
• 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]

ENSG00000224541 (HGNC:):

APP-DT (HGNC:55075): (APP divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000282 (28/991548) while in subpopulation EAS AF = 0.00089 (24/26980). AF 95% confidence interval is 0.000613. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 28 AD gene.

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.-111G>T		5_prime_UTR	Exon 1 of 18	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.-111G>T		5_prime_UTR	Exon 1 of 17	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.-111G>T		5_prime_UTR	Exon 1 of 17	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.-111G>T		5_prime_UTR	Exon 1 of 18	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.-111G>T		5_prime_UTR	Exon 1 of 17	ENSP00000350578.3	P05067-8
	APP	ENST00000348990.9	TSL:1	c.-111G>T		5_prime_UTR	Exon 1 of 16	ENSP00000345463.5	P05067-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000282 AC: 28 AN: 991548 Hom.: 0 Cov.: 13 AF XY: 0.0000324 AC XY: 16 AN XY: 493400

African (AFR) AF: 0.00 AC: 0 AN: 19636

American (AMR) AF: 0.00 AC: 0 AN: 12798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16088

East Asian (EAS) AF: 0.000890 AC: 24 AN: 26980

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3094

European-Non Finnish (NFE) AF: 0.00000254 AC: 2 AN: 787384

Other (OTH) AF: 0.0000233 AC: 1 AN: 42846

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Alzheimer disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.51
PhyloP100		0.81
PromoterAI		-0.090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs459543; hg19: chr21-27543049;