chr12-122232271-T-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_022916.6(VPS33A):āc.1766A>Gā(p.Glu589Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
VPS33A
NM_022916.6 missense
NM_022916.6 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 6.21
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34336442).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS33A | NM_022916.6 | c.1766A>G | p.Glu589Gly | missense_variant | 13/13 | ENST00000267199.9 | |
VPS33A | NM_001351018.2 | c.1733A>G | p.Glu578Gly | missense_variant | 13/13 | ||
VPS33A | NM_001351019.2 | c.1718A>G | p.Glu573Gly | missense_variant | 13/13 | ||
VPS33A | NM_001351020.2 | c.1445A>G | p.Glu482Gly | missense_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS33A | ENST00000267199.9 | c.1766A>G | p.Glu589Gly | missense_variant | 13/13 | 1 | NM_022916.6 | P1 | |
VPS33A | ENST00000643696.1 | c.1889A>G | p.Glu630Gly | missense_variant | 14/14 | ||||
VPS33A | ENST00000543633.5 | c.*1727A>G | 3_prime_UTR_variant, NMD_transcript_variant | 14/14 | 5 | ||||
VPS33A | ENST00000544349.6 | c.*1745A>G | 3_prime_UTR_variant, NMD_transcript_variant | 14/14 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460878Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726630
GnomAD4 exome
AF:
AC:
1
AN:
1460878
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726630
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2023 | The c.1766A>G (p.E589G) alteration is located in exon 13 (coding exon 13) of the VPS33A gene. This alteration results from a A to G substitution at nucleotide position 1766, causing the glutamic acid (E) at amino acid position 589 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
B;.
Vest4
MutPred
Gain of catalytic residue at I588 (P = 0.1453);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at