rs398122407

chr15-91004872-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_018668.5(VPS33B):c.1225+5G>C variant causes a splice donor 5th base, 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. 2/2 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_donor_5th_base, 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
VPS33B	NM_018668.5	c.1225+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1225+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1144+5G>C		splice_donor_5th_base_variant, intron_variant		2
VPS33B	ENST00000574755.5	c.*920+5G>C		splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant		2

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	Eurofins Ntd Llc (ga)	Sep 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2018	The c.1225+5G>C variant in the VPS33B gene has been reported previously in multiple unrelated individuals with an attenuated arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (Smith et al., 2012; Weyand et al., 2016). This variant reduces the quality of the splice donor site in intron 16, and is expected to cause abnormal gene splicing. Functional studies demonstrated that the shorter protein product of the c.1225+5G>C variant retained some ability to interact with VIPAR, and thus it retained partial wild-type function (Smith et al., 2012). The c.1225+5G>C variant is observed in 4/33582 (0.012%) alleles from individuals of Latino background, 5/246220 (0.002%) alleles in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1225+5G>C as a likely pathogenic variant. -

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	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

- -

VPS33B-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

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. -

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;