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.Trp441Ter) 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.1322G>A | p.Trp441Ter | stop_gained | 11/17 | ENST00000649063.2 | |
AP5Z1 | NM_001364858.1 | c.854G>A | p.Trp285Ter | stop_gained | 10/16 | ||
AP5Z1 | XM_047421098.1 | c.986G>A | p.Trp329Ter | stop_gained | 9/15 | ||
AP5Z1 | NR_157345.1 | n.1453G>A | non_coding_transcript_exon_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.1322G>A | p.Trp441Ter | stop_gained | 11/17 | NM_014855.3 | P1 |
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
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 28, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 02, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 375313). This premature translational stop signal has been observed in individual(s) with spastic paraplegia (PMID: 24833714). 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 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). - |
Hereditary spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | AP5Z1: PVS1, PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at