12-122232410-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_022916.6(VPS33A):c.1627C>T(p.Arg543Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VPS33A NM_022916.6 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_022916.6 Downstream stopcodon found after 7 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33A	NM_022916.6	c.1627C>T	p.Arg543Ter	stop_gained	13/13	ENST00000267199.9
VPS33A	NM_001351018.2	c.1594C>T	p.Arg532Ter	stop_gained	13/13
VPS33A	NM_001351019.2	c.1579C>T	p.Arg527Ter	stop_gained	13/13
VPS33A	NM_001351020.2	c.1306C>T	p.Arg436Ter	stop_gained	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33A	ENST00000267199.9	c.1627C>T	p.Arg543Ter	stop_gained	13/13	1	NM_022916.6	P1
VPS33A	ENST00000643696.1	c.1750C>T	p.Arg584Ter	stop_gained	14/14
VPS33A	ENST00000543633.5	c.*1588C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14	5
VPS33A	ENST00000544349.6	c.*1606C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459394 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725838

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 16, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with VPS33A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg543*) in the VPS33A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the VPS33A protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	D
Vest4		0.30
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122716957;