12-122232876-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022916.6(VPS33A):c.1533C>G(p.Ile511Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,806 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

VPS33A
NM_022916.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0890

Variant links:

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]

VPS33A links:

Genome browser will be placed here

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=0.3170576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VPS33A	NM_022916.6 linkuse as main transcript	c.1533C>G	p.Ile511Met	missense_variant	12/13	ENST00000267199.9
VPS33A	NM_001351018.2 linkuse as main transcript	c.1500C>G	p.Ile500Met	missense_variant	12/13
VPS33A	NM_001351019.2 linkuse as main transcript	c.1485C>G	p.Ile495Met	missense_variant	12/13
VPS33A	NM_001351020.2 linkuse as main transcript	c.1212C>G	p.Ile404Met	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33A	ENST00000267199.9 linkuse as main transcript	c.1533C>G	p.Ile511Met	missense_variant	12/13	1	NM_022916.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249670

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Jul 25, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the VPS33A protein (p.Ile511Met). This variant is present in population databases (rs770725073, gnomAD 0.002%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.7

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

N;.;.

REVEL

Uncertain

0.54

Sift

Benign

0.081

T;.;.

Sift4G

Benign

0.21

T;.;.

Polyphen

0.89

P;.;.

Vest4

0.78

MutPred

0.46

Gain of catalytic residue at I511 (P = 0.0057);.;.;

MVP

0.61

MPC

1.1

ClinPred

0.65

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over