chr12-122232860-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_022916.6(VPS33A):c.1549A>C(p.Ile517Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
VPS33A
NM_022916.6 missense
NM_022916.6 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 4.99
Genes affected
VPS33A (HGNC:18179): (VPS33A core subunit of CORVET and HOPS complexes) This gene encodes a tethering protein and a core subunit of the homotypic fusion and protein sorting (HOPS) complex. The HOPS complex and a second endosomal tethering complex called the class C core vacuole/endosome tethering (CORVET) complex, perform diverse functions in endocytosis including membrane tethering, RabGTPase interaction, activation and proofreading of synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) assembly to drive membrane fusion, and endosome-to-cytoskeleton attachment. The HOPS complex controls endosome maturation as well as endosome traffic to the lysosome. This complex is essential for vacuolar fusion and is required for adaptor protein complex 3-dependent transport from the golgi to the vacuole. The encoded protein belongs to the Sec1/Munc18 (SM) family of SNARE-mediated membrane fusion regulators. Naturally occurring mutations in this gene are associated with a novel mucopolysaccharidosis-like disease. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15263137).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS33A | NM_022916.6 | c.1549A>C | p.Ile517Leu | missense_variant | 12/13 | ENST00000267199.9 | |
VPS33A | NM_001351018.2 | c.1516A>C | p.Ile506Leu | missense_variant | 12/13 | ||
VPS33A | NM_001351019.2 | c.1501A>C | p.Ile501Leu | missense_variant | 12/13 | ||
VPS33A | NM_001351020.2 | c.1228A>C | p.Ile410Leu | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS33A | ENST00000267199.9 | c.1549A>C | p.Ile517Leu | missense_variant | 12/13 | 1 | NM_022916.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250532Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135592
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GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45AN XY: 727220
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The c.1549A>C (p.I517L) alteration is located in exon 12 (coding exon 12) of the VPS33A gene. This alteration results from a A to C substitution at nucleotide position 1549, causing the isoleucine (I) at amino acid position 517 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 517 of the VPS33A protein (p.Ile517Leu). This variant is present in population databases (rs750798693, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with VPS33A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2179402). 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 VPS33A 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.
REVEL
Benign
Sift
Benign
T;.;.
Sift4G
Benign
T;.;.
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at