12-122232297-T-A

Variant names:

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.570

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:

ENSG00000256861 (HGNC:):

ENSG00000256861 links:

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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 rank	MANE	Protein
VPS33A	NM_022916.6 link	c.1740A>T	p.Lys580Asn	missense_variant	Exon 13 of 13	ENST00000267199.9	NP_075067.2
VPS33A	NM_001351018.2 link	c.1707A>T	p.Lys569Asn	missense_variant	Exon 13 of 13		NP_001337947.1
VPS33A	NM_001351019.2 link	c.1692A>T	p.Lys564Asn	missense_variant	Exon 13 of 13		NP_001337948.1
VPS33A	NM_001351020.2 link	c.1419A>T	p.Lys473Asn	missense_variant	Exon 11 of 11		NP_001337949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33A	ENST00000267199.9 link	c.1740A>T	p.Lys580Asn	missense_variant	Exon 13 of 13	1	NM_022916.6	ENSP00000267199.3		Q96AX1
ENSG00000256861	ENST00000535844.1 link	n.1594+29A>T		intron_variant	Intron 12 of 15	2		ENSP00000454454.1		H3BMM5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VPS33A-related conditions. 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

Pathogenic

0.64

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.16

Sift

Benign

0.16

T;.

Sift4G

Benign

0.11

T;.

Polyphen

0.88

P;.

Vest4

0.75

MutPred

0.55

Loss of ubiquitination at K580 (P = 0.0148);.;

MVP

0.15

MPC

0.83

ClinPred

0.98

GERP RS

-3.4

Varity_R

0.55

gMVP

0.95

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