chr12-122232297-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_022916.6(VPS33A):c.1740A>T(p.Lys580Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
VPS33A
NM_022916.6 missense
NM_022916.6 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: -0.570
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS33A | NM_022916.6 | c.1740A>T | p.Lys580Asn | missense_variant | 13/13 | ENST00000267199.9 | |
VPS33A | NM_001351018.2 | c.1707A>T | p.Lys569Asn | missense_variant | 13/13 | ||
VPS33A | NM_001351019.2 | c.1692A>T | p.Lys564Asn | missense_variant | 13/13 | ||
VPS33A | NM_001351020.2 | c.1419A>T | p.Lys473Asn | missense_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS33A | ENST00000267199.9 | c.1740A>T | p.Lys580Asn | missense_variant | 13/13 | 1 | NM_022916.6 | P1 | |
VPS33A | ENST00000643696.1 | c.1863A>T | p.Lys621Asn | missense_variant | 14/14 | ||||
VPS33A | ENST00000543633.5 | c.*1701A>T | 3_prime_UTR_variant, NMD_transcript_variant | 14/14 | 5 | ||||
VPS33A | ENST00000544349.6 | c.*1719A>T | 3_prime_UTR_variant, NMD_transcript_variant | 14/14 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 exome
AF:
AC:
1
AN:
1461826
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727198
Gnomad4 AFR exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2022 | 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. 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. This variant has not been reported in the literature in individuals affected with VPS33A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 580 of the VPS33A protein (p.Lys580Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
P;.
Vest4
MutPred
Loss of ubiquitination at K580 (P = 0.0148);.;
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