rs373919408
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014855.3(AP5Z1):c.1322G>A(p.Trp441*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,552,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014855.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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AP5Z1 | NM_014855.3 | c.1322G>A | p.Trp441* | stop_gained | Exon 11 of 17 | ENST00000649063.2 | NP_055670.1 | |
AP5Z1 | NM_001364858.1 | c.854G>A | p.Trp285* | stop_gained | Exon 10 of 16 | NP_001351787.1 | ||
AP5Z1 | XM_047421098.1 | c.986G>A | p.Trp329* | stop_gained | Exon 9 of 15 | XP_047277054.1 | ||
AP5Z1 | NR_157345.1 | n.1453G>A | non_coding_transcript_exon_variant | Exon 11 of 17 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000508 AC: 8AN: 157600Hom.: 0 AF XY: 0.0000358 AC XY: 3AN XY: 83754
GnomAD4 exome AF: 0.0000886 AC: 124AN: 1400210Hom.: 0 Cov.: 31 AF XY: 0.0000868 AC XY: 60AN XY: 691058
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74322
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 48 Pathogenic:3
This sequence change creates a premature translational stop signal (p.Trp441*) in the AP5Z1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP5Z1 are known to be pathogenic (PMID: 20613862, 27606357). 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 premature translational stop signal has been observed in individual(s) with spastic paraplegia (PMID: 24833714). ClinVar contains an entry for this variant (Variation ID: 375313). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary spastic paraplegia Pathogenic:1
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not provided Pathogenic:1
AP5Z1: PVS1, PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at