rs1554257381
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014855.3(AP5Z1):c.355_358dup(p.Leu120SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,570,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
AP5Z1
NM_014855.3 frameshift
NM_014855.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.478
Genes affected
AP5Z1 (HGNC:22197): (adaptor related protein complex 5 subunit zeta 1) This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862). [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-4781741-T-TTCTC is Pathogenic according to our data. Variant chr7-4781741-T-TTCTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.355_358dup | p.Leu120SerfsTer6 | frameshift_variant | 3/17 | ENST00000649063.2 | |
AP5Z1 | NM_001364858.1 | c.-103+431_-103+434dup | intron_variant | ||||
AP5Z1 | NR_157345.1 | n.448_451dup | non_coding_transcript_exon_variant | 3/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.355_358dup | p.Leu120SerfsTer6 | frameshift_variant | 3/17 | NM_014855.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000120 AC: 17AN: 1418456Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 8AN XY: 697554
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 26, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2017 | The c.355_358dupCTCT variant in the AP5Z1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.355_358dupCTCT variant causes a frameshift starting with codon Leucine 120, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Leu120SerfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.355_358dupCTCT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.355_358dupCTCT as a likely pathogenic variant. - |
Hereditary spastic paraplegia 48 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 01, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 446850). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu120Serfs*6) 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). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at