NM_014855.3:c.874C>T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014855.3(AP5Z1):c.874C>T(p.Arg292Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,611,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014855.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.874C>T | p.Arg292Trp | missense_variant | Exon 7 of 17 | ENST00000649063.2 | NP_055670.1 | |
AP5Z1 | NM_001364858.1 | c.406C>T | p.Arg136Trp | missense_variant | Exon 6 of 16 | NP_001351787.1 | ||
AP5Z1 | XM_047421098.1 | c.538C>T | p.Arg180Trp | missense_variant | Exon 5 of 15 | XP_047277054.1 | ||
AP5Z1 | NR_157345.1 | n.967C>T | non_coding_transcript_exon_variant | Exon 7 of 17 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000293 AC: 71AN: 242706Hom.: 0 AF XY: 0.000248 AC XY: 33AN XY: 133306
GnomAD4 exome AF: 0.000358 AC: 523AN: 1459350Hom.: 1 Cov.: 32 AF XY: 0.000321 AC XY: 233AN XY: 725930
GnomAD4 genome AF: 0.000348 AC: 53AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Hereditary spastic paraplegia 48 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 292 of the AP5Z1 protein (p.Arg292Trp). This variant is present in population databases (rs199760184, gnomAD 0.06%). This missense change has been observed in individual(s) with complicated hereditary spastic paraplegia (PMID: 25333062). ClinVar contains an entry for this variant (Variation ID: 580702). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Inborn genetic diseases Uncertain:1
Schlipf, 2014 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hereditary spastic paraplegia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at