rs554060393
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014855.3(AP5Z1):c.838A>C(p.Thr280Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,611,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T280A) has been classified as Likely benign.
Frequency
Consequence
NM_014855.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.838A>C | p.Thr280Pro | missense_variant | 7/17 | ENST00000649063.2 | |
AP5Z1 | NM_001364858.1 | c.370A>C | p.Thr124Pro | missense_variant | 6/16 | ||
AP5Z1 | XM_047421098.1 | c.502A>C | p.Thr168Pro | missense_variant | 5/15 | ||
AP5Z1 | NR_157345.1 | n.931A>C | non_coding_transcript_exon_variant | 7/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.838A>C | p.Thr280Pro | missense_variant | 7/17 | NM_014855.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152030Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000177 AC: 43AN: 243130Hom.: 0 AF XY: 0.000173 AC XY: 23AN XY: 133230
GnomAD4 exome AF: 0.000123 AC: 180AN: 1459620Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 100AN XY: 726028
GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74390
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 48 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 280 of the AP5Z1 protein (p.Thr280Pro). This variant is present in population databases (rs554060393, gnomAD 0.05%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 28832565). ClinVar contains an entry for this variant (Variation ID: 424671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AP5Z1 protein function with a negative predictive value of 80%. 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. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde | Mar 07, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 27, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at