rs764332870
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014855.3(AP5Z1):c.1601C>T(p.Ala534Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 1,604,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A534S) 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.1601C>T | p.Ala534Val | missense_variant | 13/17 | ENST00000649063.2 | |
AP5Z1 | NM_001364858.1 | c.1133C>T | p.Ala378Val | missense_variant | 12/16 | ||
AP5Z1 | XM_047421098.1 | c.1265C>T | p.Ala422Val | missense_variant | 11/15 | ||
AP5Z1 | NR_157345.1 | n.1732C>T | non_coding_transcript_exon_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.1601C>T | p.Ala534Val | missense_variant | 13/17 | NM_014855.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000473 AC: 11AN: 232524Hom.: 0 AF XY: 0.0000548 AC XY: 7AN XY: 127784
GnomAD4 exome AF: 0.0000468 AC: 68AN: 1452226Hom.: 0 Cov.: 31 AF XY: 0.0000526 AC XY: 38AN XY: 721920
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74316
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 15, 2016 | - - |
Hereditary spastic paraplegia 48 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 534 of the AP5Z1 protein (p.Ala534Val). This variant is present in population databases (rs764332870, gnomAD 0.03%). 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: 446847). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at