rs398122407

Positions:

• chr15-91004872-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_018668.5(VPS33B):​c.1225+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000342 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VPS33B NM_018668.5 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.88

Genes affected

VPS33B (HGNC:12712): (VPS33B late endosome and lysosome associated) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ENSG00000284946 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-91004872-C-G is Pathogenic according to our data. Variant chr15-91004872-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91004872-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1225+5G>C		splice_region_variant, intron_variant		ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1225+5G>C		splice_region_variant, intron_variant		1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1225+5G>C		splice_region_variant, intron_variant				ENSP00000494429.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251450 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 08, 2023	This variant has been observed in individual(s) with VPS33B-related conditions (PMID: 22753090, 26505894, 29907094, 31343487). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 88858). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change falls in intron 16 of the VPS33B gene. It does not directly change the encoded amino acid sequence of the VPS33B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs398122407, gnomAD 0.01%). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2024	RNA studies demonstrate a damaging effect: shortened protein length (PMID: 22753090); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33029437, 22753090, 26505894, 31589614, 31343487, 31463586, 29907094, 31240160) -

Arthrogryposis, renal dysfunction, and cholestasis 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

VPS33B-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

The VPS33B c.1225+5G>C variant is predicted to interfere with splicing. This variant has been reported to be pathogenic for a mild arthrogryposis-renal dysfunction-cholestasis (ARC) phenotype (Smith et al. 2012. PubMed ID: 22753090; Rosales et al. 2018. PubMed ID: 29907094). A functional study showed that this splicing variant results in a truncated protein with partially reduced activity (Smith et al. 2012. PubMed ID: 22753090). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/88858). Given all the evidence, we interpret c.1225+5G>C as pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The c.1225+5G>C intronic alteration results from a G to C substitution 5 nucleotides after coding exon 16 of the VPS33B gene. Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/251450) total alleles studied. The highest observed frequency was 0.012% (4/34590) of Latino alleles. This variant has been identified in conjunction with other VPS33B variants in individuals reported to have an attenuated clinical presentation including developmental delay, sensorineural hearing loss, renal dysfunction, nephrotic syndrome, knee contractures, rocker bottom feet, cholestasis, mild arthrogryposis, and other clinical features consistent with VPS33B-related arthrogryposis, renal dysfunction, and cholestasis syndrome; in at least one instance, the variants were identified in trans (Smith, 2012; Weyand, 2016; Rosales, 2018; Agawu, 2019; Duong, 2020). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122407; hg19: chr15-91548102;