NM_000484.4:c.*7G>A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000484.4(APP):c.*7G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,188 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
Consequence
NM_000484.4 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APP | NM_000484.4 | c.*7G>A | 3_prime_UTR_variant | Exon 18 of 18 | ENST00000346798.8 | NP_000475.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000270 AC: 41AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251180Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135778
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460994Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 726882
GnomAD4 genome AF: 0.000276 AC: 42AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74418
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: APP c.*7G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 5.2e-05 in 251180 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in APP causing Cerebral Amyloid Angiopathy, APP-Related, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.*7G>A in individuals affected with Cerebral Amyloid Angiopathy, APP-Related and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 897922). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Alzheimer disease Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at