chr12-122232847-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_022916.6(VPS33A):c.1562C>T(p.Pro521Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P521R) has been classified as Uncertain significance.
Frequency
Consequence
NM_022916.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS33A | NM_022916.6 | c.1562C>T | p.Pro521Leu | missense_variant | 12/13 | ENST00000267199.9 | |
VPS33A | NM_001351018.2 | c.1529C>T | p.Pro510Leu | missense_variant | 12/13 | ||
VPS33A | NM_001351019.2 | c.1514C>T | p.Pro505Leu | missense_variant | 12/13 | ||
VPS33A | NM_001351020.2 | c.1241C>T | p.Pro414Leu | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS33A | ENST00000267199.9 | c.1562C>T | p.Pro521Leu | missense_variant | 12/13 | 1 | NM_022916.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250604Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135602
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727186
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 06, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the VPS33A protein (p.Pro521Leu). This variant is present in population databases (rs751768352, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with VPS33A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at