rs147369435
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014855.3(AP5Z1):c.2287G>A(p.Val763Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,612,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014855.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.2287G>A | p.Val763Met | missense_variant | Exon 17 of 17 | ENST00000649063.2 | NP_055670.1 | |
AP5Z1 | NM_001364858.1 | c.1819G>A | p.Val607Met | missense_variant | Exon 16 of 16 | NP_001351787.1 | ||
AP5Z1 | XM_047421098.1 | c.1951G>A | p.Val651Met | missense_variant | Exon 15 of 15 | XP_047277054.1 | ||
AP5Z1 | NR_157345.1 | n.2418G>A | non_coding_transcript_exon_variant | Exon 17 of 17 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000113 AC: 28AN: 247596Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 134860
GnomAD4 exome AF: 0.0000924 AC: 135AN: 1460428Hom.: 0 Cov.: 32 AF XY: 0.0000922 AC XY: 67AN XY: 726482
GnomAD4 genome AF: 0.000158 AC: 24AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:4
- -
- -
- -
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 uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -
Hereditary spastic paraplegia 48 Uncertain:3
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 763 of the AP5Z1 protein (p.Val763Met). This variant is present in population databases (rs147369435, gnomAD 0.02%). 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: 412232). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 specified Uncertain:1
Variant summary: KIAA0415 c.2287G>A (p.Val763Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 247596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2287G>A has been reported in the literature in at-least one individual affected with Hereditary Spastic Paraplegia (example: DAmore_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 48. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at