chr7-4783465-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014855.3(AP5Z1):c.511+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,340 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_014855.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.511+5G>A | splice_region_variant, intron_variant | Intron 4 of 16 | ENST00000649063.2 | NP_055670.1 | ||
AP5Z1 | NM_001364858.1 | c.43+5G>A | splice_region_variant, intron_variant | Intron 3 of 15 | NP_001351787.1 | |||
AP5Z1 | XM_047421098.1 | c.175+5G>A | splice_region_variant, intron_variant | Intron 2 of 14 | XP_047277054.1 | |||
AP5Z1 | NR_157345.1 | n.604+5G>A | splice_region_variant, intron_variant | Intron 4 of 16 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246286Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134186
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1458282Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 725122
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 48 Uncertain:2
This sequence change falls in intron 4 of the AP5Z1 gene. It does not directly change the encoded amino acid sequence of the AP5Z1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 360311). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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